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Volume 1, 2004
Contents
Preface
Atta-ur-Rahman, Allen B. Reitz
Targeting Protein Kinases for Bone Disease:
Discovery and Development of Src Inhibitors Pp. 3-27
Chester A. Metcalf III, Marie Rose van Schravendijk,
David C. Dalgarno and Tomi K. Sawyer
[Abstract]
Inhibitors of Matrix Metalloproteinases: Design,
Structure and Therapeutic Applications Pp. 29-75
Jerry W. Skiles, Nina C. Gonnella and Arco Y. Jeng
[Abstract]
Mechanism-based Inhibition of Metalloproteinases Pp. 77-83
Dong H. Kim and Shahriar Mobashery
[Abstract]
Selective COX-2 Inhibitors and Dual Acting Anti-inflammatory
Drugs: Critical Remarks Pp. 85-95
A. Bertolini, A. Ottani and M. Sandrini
[Abstract]
Protein Farnesyltransferase Inhibitors Pp. 97-128
Semiramis Ayral-Kaloustian and Edward J. Salaski
[Abstract]
The Design of Competitive, Small-molecule Inhibitors
of Coagulation Factor Xa Pp. 129-152
Henry W. Pauls, William R. Ewing and Yong Mi Choi-Sledeski
[Abstract]
Small Molecule Activators of the Insulin Receptor:
Potential New Therapeutic Agents for the Treatment of Diabetes Mellitus
Pp. 153-164
Edgardo Laborde and
Vara Prasad Manchem
[Abstract]
Current Therapies and Emerging Targets for the
Treatment of Diabetes
Pp. 165-187
Allan S. Wagman and John M. Nuss
[Abstract]
Designed Enediyne Antitumor Agents Pp. 189-214
G.B. Jones and F.S. Fouad
[Abstract]
Combinatorial Approaches in Anticancer Drug
Discovery: Recent Advances in Design and Synthesis Pp. 215-235
Sukanta Bhattacharyya
[Abstract]
The Expanding Role of NMR in Rational Drug Design
Pp. 237-271
Rickey P. Hicks and
Daniel A. Nichols
[Abstract]
Mass Spectrometry Based Assays for Drug Screening
in the Early Phases of Drug Discovery Pp. 273-292
Marshall M. Siegel
[Abstract]
Recent Advances in PDE4 Inhibitors as Immunoregulators
and Anti-inflammatory Drugs Pp. 293-345
Catherine Burnouf, Ingrid Devillers and Marie-Pierre Pruniaux
[Abstract]
Serotonin Reuptake Inhibition: An Update on
Current Research Strategies
Pp. 347-359
D. Spinks and G.
Spinks
[Abstract]
Emerging b-Amyloid Therapies for the Treatment of Alzheimer’s
Disease Pp. 361-384
Kelly A. Conway, Ellen W. Baxter, Kevin M. Felsenstein
and Allen B. Reitz
[Abstract]
Oxidative Stress in Animal Models of Accelerated
Aging, Alzheimer’s Disease and Huntington’s Disease Pp. 385-397
D. Allan Butterfield
[Abstract]
Constitutive Activity of Brain Serotonin Receptors:
Inverse Agonist Activity of Antipsychotic Drugs Pp. 399-408
Anil Purohit, Katharine Herrick-Davis and Milt Teitler
[Abstract]
Physicochemical Profiling (Solubility, Permeability
and Charge State) Pp. 409-475
Alex Avdeef
[Abstract]
Non-peptide Opioid Receptor Ligands - Recent
Advances. Part I - Agonists
Pp. 477-500
Agnieszka Kaczor and Dariusz Matosiuk
[Abstract]
Nitric Oxide Therapies in Vascular Diseases Pp. 501-512
E.M. Kurowska
[Abstract]
Strategies to Improve Stability and Bioavailability
of Peptide Drugs Pp. 513-528
Celine Adessi and Claudio Soto
[Abstract]
The Role of Genomics in the Discovery of Novel
Antibacterial Targets
Pp. 529-542
Jerry M. Buysse
[Abstract]
New Anti-HIV Agents in Preclinical or Clinical
Development Pp.
543-579
Erik De Clercq
[Abstract]
DNA Minor Groove Alkylators Pp. 581-594
William A. Denny
[Abstract]
Applications of Small Molecule Crystallography
and the Cambridge Structural Database in Drug Design Pp. 595-606
Johan Wouters and
Frederic Ooms
[Abstract]
Compound Optimization in Early and Late Phase
Drug Discovery: Acceptable Pharmacokinetic Properties Utilizing
Combined Physicochemical, In Vitro and In Vivo Screens Pp. 607-618
Gary W. Caldwell
[Abstract]
DNA-binding of Drugs Used in Medicinal Therapies
Pp. 619-645
G. Bischoff, S. Hoffmann, R. Zhdanov
[Abstract]
The Contribution of Combinatorial Chemistry
to Lead Generation: An Interim Analysis Pp. 647-662
Anton E.P. Adang, Pedro H.H. Hermkens
[Abstract]
New Paradigms in Drug Design and Discovery Pp. 663-681
Joseph J. Barchi, Jr. and Nouri Neama
[Abstract]
Abstracts
[Back to top] Preface
Atta-ur-Rahman, Allen B. Reitz
Medicinal Chemistry has matured as a discipline, and
there is no better time than the present to be a medicinal chemist.
One of the primary driving forces in this renaissance is the increased
value added by collaborations with biology, pharmacology, toxicology,
spectroscopy, and allied fields earlier in the drug discovery process.
The modern practicing medicinal chemist is inundated with new data,
including in vitro and in vivo ADME profiling, which enables informed
decisions that increase the likelihood of success in the future.
This first issue of Frontiers in Medicinal Chemistry is being published
only online, allowing for rapid and broad dissemination of the material
presented. The chapters are selected from issues of Current Medicinal
Chemistry, Current Topics in Medicinal Chemistry and Current Pharmaceutical
Design to represent a cross-section of the most compelling subjects
and developments in medicinal and bioorganic chemistry. The manuscripts
and topics are clustered thematically, and overall constitute a
substantial and impressive body of knowledge. The authors were given
the opportunity to update their contributions, and many chose to
do that. It is expected that Frontiers will be published on an annual
basis in future years. Our thanks to Matthew Honan of Bentham Science
Publishers for providing this opportunity.
[Back
to top]
Targeting Protein Kinases for Bone Disease: Discovery and Development
of Src Inhibitors
Chester A. Metcalf III, Marie Rose van Schravendijk,
David C. Dalgarno and Tomi K. Sawyer
The dynamic and highly regulated processes of bone
remodeling involve two major cells, osteoclasts and osteoblasts,
both of which command a multitude of cellular signaling pathways
involving protein kinases. Of the possible kinases in these cells,
Src tyrosine kinase stands out as a promising therapeutic target
for bone disease as validated by Src knockout mouse studies and
in vitro cellular experiments, suggesting a regulatory role for
Src in both osteoclasts (positive) and osteoblasts (negative). Advances
in structural studies involving both Src and non-Src family kinases,
in activated and unactivated protein states, have uncovered key
binding site interactions that have led to the design of potent
Src inhibitors. The lead compounds originate from a variety of synthetic
templates and have demonstrated nM potency in enzymatic/binding
assays and efficacy in animal models of bone disease. This review
will provide a current understanding of critical Src signalling
pathways in osteoclasts and osteoblasts, while detailing the structure-based
design and screening-based lead discovery of Src inhibitors to be
developed as therapeutic agents for bone disease.
[Back
to top]
Inhibitors of Matrix Metalloproteinases: Design, Structure and Therapeutic
Applications
Jerry W. Skiles, Nina C. Gonnella and Arco Y. Jeng
Matrix metalloproteinases (MMPs) are a family of
zinc-containing enzymes involved in the degradation and remodeling
of extracellular matrix proteins. The activities of these enzymes
are well regulated by endogenous tissue inhibitors of metalloproteinases
(TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs
has been implicated in the pathogenesis of a variety of diseases
such as cancer, osteoarthritis, and rheumatoid arthritis. Thus,
MMP inhibitors are expected to be useful for the treatment of these
disorders. This article reviews briefly the biochemistry of MMPs
and evidence for their pathogenic roles using molecular biology
approaches. Biomolecular structures used in the design of MMP inhibitors
are thoroughly covered. Major emphasis is on recently published
potent, small molecular weight MMP inhibitors and their pharmacological
properties. Finally, available clinical results of compounds in
development are summarized.
[Back to top]
Mechanism-based Inhibition of Metalloproteinases
Dong H. Kim and Shahriar Mobashery
The functions of zinc proteases have been implicated
in a host of physiological and pathological processes in living
organisms. Mechanism-based inhibitors are highly sought as biologically
active molecules that afford high selectivity in targeting specific
enzymes. Mechanism-based inhibitors for zincdependent
proteases have been developed in the past several years.
These inhibitors exploit the chemistry inherent to transition metals
in their mechanisms of enzyme inhibition. These efforts have been
reviewed in this manuscript.
[Back
to top]
Selective COX-2 Inhibitors and Dual Acting Anti-inflammatory Drugs:
Critical Remarks
A. Bertolini, A. Ottani and M. Sandrini
Non steroidal anti-inflammatory drugs (NSAIDs)
are still the most commonly used remedies for rheumatic diseases.
But NSAIDs produce serious adverse effects, the most important being
gastric injury up to gastric ulceration and renal damage.
Several strategies have been adopted in order to avoid
these shortcomings, expecially gastrointestinal toxicity. So, non
steroidal anti-inflammatory drugs have been associated with gastroprotective
agents that counteract the damaging effects of prostaglandin synthesis
suppression: however, a combination therapy introduces problems
of pharmacokinetics, toxicity, and patient’s compliance. Also
incorporation of a nitric oxide (NO)-generating moiety into the
molecule of several NSAIDs was shown to greatly attenuate their
ulcerogenic activity: however, several findings suggest a possible
involvement of NO in the pathogenesis of arthritis and subsequent
tissue destruction.
A most promising approach seemed to be the preparation
of novel NSAIDs, specific for the inducible isoform of cyclooxygenase
(COX-2): they appear to be devoid of gastrointestinal toxicity,
in that they spare mucosal prostaglandin synthesis.
However, a number of recent studies raised serious questions
about the two central tenets that support this approach, namely
that the prostaglandins that mediate inflammation and pain are produced
solely via COX-2 and that the prostaglandins that are important
in gastrointestinal and renal function are produced solely via COX-1.
So, increasing evidence shows that COX-2 (not only COX-1) also plays
a physiological role in several body functions and that, conversely,
COX-1 (not only COX-2) may also be induced at sites of inflammation.
Moreover, COX-2 selective NSAIDs have lost the cardiovascular
protective effects of non-selective NSAIDs, effects which are mediated
through COX-1 inhibition (in addition, COX-2 has a role in sustaining
vascular prostacyclin production).
The products generated by the 5-lipoxygenase pathway
(leukotrienes) are particularly important in inflammation: indeed,
leukotrienes increase microvascular permeability and are potent
chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly
reduces the expression of TNF-a(a
cytokine that plays a key role in inflammation). This explains the
efforts to obtain drugs able to inhibit both 5-lipoxygenase and
cyclooxygenases: the so-called dual acting anti-inflammatory drugs.
Such compounds retain the activity of classical NSAIDs, while avoiding
their main drawbacks, in that curtailed production of gastroprotective
prostaglandins is associated with a concurrent curtailed production
of the gastro-damaging and bronchoconstrictive leukotrienes.
Moreover, thanks to their mechanism of action, dual acting
anti-inflammatory drugs could not merely alleviate symptoms of rheumatic
diseases, but might also satisfy, at least in part, the criteria
of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase
microvascular permeability, are potent chemotactic agents and attract
eosinophils, neutrophils and monocytes into the synovium.
Finally, recent data strongly suggest that dual inhibitors
may have specific protective activity also in neurodegeneration.
[Back
to top]
Protein Farnesyltransferase Inhibitors
Semiramis Ayral-Kaloustian and Edward J. Salaski
Specific mutations in the ras gene impair the
guanosine triphophatase (GTPase) activity of Ras proteins, which
play a fundamental role in the signaling cascade, leading to uninterrupted
growth signals and to the transformation of normal cells into malignant
phenotypes. It has been shown that normal cells transfected with mutant ras gene become cancerous
and that unfarnesylated, cytosolic mutant Ras protein does not anchor
onto cell membranes and cannot induce this transformation. Posttranslational
modification and plasma membrane association of mutant Ras is necessary
for this transforming activity. Since its
identification, the enzyme protein farnesyltransferase (FTase)
that catalyzes the first and essential step of the three Ras processing
steps has emerged as the most promising target for therapeutic intervention.
Ftase has been implicated as a potential target in inhibiting the
prenylation of a variety of proteins, thus in
controlling varied disease states (e.g. cancer, neurofibromatosis,
restenosis, viral hepatitis, bone resorption, parasitic infections,
corneal inflammations, and diabetes) associated with prenyl modifications
of Ras and other proteins. Furthermore, it has been suggested that
FTase inhibitors indirectly help in inhibiting tumors via suppression
of angiogenesis and induction of apoptosis. Major milestones have
been achieved with small-molecule FTase inhibitors that show efficacy
without toxicity in vitro, as well as in mouse models bearing ras-dependent
tumors. With the determination of the crystal structure of mammalian
FTase, existent leads have been fine-tuned and new potent molecules
of diverse structural classes have been designed. Extensive in vitro
and in vivo studies with these inhibitors have revealed the complexities
of the signaling cascade involving FTase, and shed more light on
possible modes of tumor inhibition, without providing a clear-cut
mechanism of action. A few of these molecules are currently in the
clinic, with at least three drug candidates in Phase II studies
and two in Phase III. This article will review the progress that
has been reported with FTase inhibitors in drug discovery and in
the clinic.
[Back
to top]
The Design of Competitive, Small-molecule Inhibitors of Coagulation
Factor Xa
Henry W. Pauls, William R. Ewing and Yong Mi Choi-Sledeski
The last five years has seen an explosion of research
into inhibitors of Factor Xa as potential antithrombotic agents.
Aventis Pharma through its founder company Rhone-Poulenc Rorer was
a participant in this effort and contributed significantly to the
discovery of new inhibitors in recent years. This chapter traces
the systematic development of the former Rhone-Poulenc
Rorer factor Xa program from conception to the realization of potent,
orally bioavailable inhibitors with exquisite selectivity against
other serine proteases. The work on b- aminoesters described in Part 1 culminates
in the development of FXV673 (Ki = 0.5 nM), an effective anticoagulant
for acute indications. Part 2.2 details the de novo design of a
pyrrolidinone series of inhibitors, within which a group of efficacious
i.v. agents were identified (e.g RPR130737, Ki = 2 nM). The first
active and bioavailable benzamidine isostere i.e. the 1-aminoisoquinoline
(RPR208815, Ki = 22 nM) was discovered on the pyrrolidinone scaffold
(Part 2.3). Ultimately a variety of benzamidine mimics were explored
and incorporated into the ketopiperazine series (Part 3); the 6-substituted
aminoquinazolines were found to be subnanomolar against factor Xa
and highly selective. The azaindole moiety stands out as imparting
favorable pharmacokinetic properties to the sulfonamido-ketopiperazines;
RPR209685, a potent representative (Ki = 1 nM), was shown to be
orally efficacious in the dog.
[Back
to top]
Small Molecule Activators of the Insulin Receptor: Potential New
Therapeutic Agents for the Treatment of Diabetes Mellitus
Edgardo Laborde and
Vara Prasad Manchem
Diabetes Mellitus refers to a spectrum of syndromes
characterized by abnormally high levels of glucose in blood. These
syndromes are associated with an absolute (Type 1 diabetes) or relative
(Type 2 diabetes) deficiency of insulin, coupled with varying degrees
of peripheral resistance to the actions of insulin. Clinical studies
have shown that controlling hyperglycemia significantly reduces
the appearance and progression of the vascular complications associated
with diabetes. Insulin's regulation of glucose homeostasis is mediated
by acascade of signaling events that take place upon insulin binding
to its cell surface receptor. Autophosphorylation of the receptor
and activation of its intrinsic tyrosine kinase are critical processes
for transmitting these intracellular signals. Type 1 diabetes patients
depend on exogenous insulin to achieve these effects, whereas Type
2 diabetes patients can accomplish a similar response through oral
medications that increase the production of endogenous insulin or
enhance its actions on the target tissues. Current biochemical and
clinical evidence suggests that defects within the insulin receptor
itself may be a cause of insulin resistance leading to Type 2 diabetes.
This review focuses on the insulin receptor as a target for therapeutic
intervention, and describes the recent discovery of small molecules
that act on the receptor and either enhance or directly emulate
the actions of insulin both in vitro and in vivo.
[Back
to top]
Current Therapies and Emerging Targets for the Treatment of Diabetes
Allan S. Wagman and John M. Nuss
Concurrent with the spread of the western lifestyle,
the prevalence of all types of diabetes is on the rise in the world's
population. The number of diabetics is increasing by 4-5% per year
with an estimated 40-45% of individual's over the age of 65 years
having either type II diabetes or impaired glucose tolerance. Since
the signs of diabetes are not immediately obvious, diagnosis can
be preceded by an extended period of impaired glucose tolerance
resulting in the prevalence of beta-cell dysfunction and macrovascular
complications. In addition to increased medical vigilance, diabetes
is being combated through aggressive treatment directed at lowering
circulating blood glucose and inhibiting postprandial hyperglycemic
spikes. Current strategies to treat diabetes include reducing insulin
resistance using glitazones, supplementing insulin supplies with
exogenous insulin, increasing endogenous insulin production with
sulfonylureas and meglitinides, reducing hepatic glucose production
through biguanides, and limiting postprandial glucose absorption
with alpha-glucosidase inhibitors. In all of these areas, new generations
of small molecules are being investigated which exhibit improved
efficacy and safety profiles. Promising biological targets are also
emerging such as (1) insulin sensitizers including protein tyrosine
hosphatase-1B (PTP- 1B) and glycogen synthase kinase 3 (GSK3), (2)
inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase
(PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including
carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5)
energy expenditure by means of beta 3-adrenoceptor agonists. Also
important are alternative routes of glucose disposal such as Na+-glucose
cotransporter (SGLT) inhibitors, combination therapies, and the
treatment of diabetic complications (eg. retinopathy, nephropathy,
and neuropathy). With may new opportunities for drug discovery,
the prospects are excellent for development of innovative therapies
to effectively manage diabetes and prevent its long term complications.
This review highlights recent (1997-2000) advances in diabetes therapy
and research with an emphasis on small molecule drug design (275
references).
[Back to top]
Designed Enediyne Antitumor Agents
G.B. Jones and F.S. Fouad
The enediynes remain among the most potent antitumoral
agents to have been discovered in the past decade. Following prodrug
activation, the enediynes undergo cycloaromatization reactions resulting
in formation of highly reactive diradical intermediates. The diradical
species engage in atomtransfer chemistry to produce neutral arene
products, in the process inducing damage to key macromolecules.
Several of the naturally occurring members of the enediyne family
of antibiotics have entered clinical trials, and this has prompted
the design of synthetic enediynes, where the enediyne 'warhead'
is conjugated to a targeted delivery vehicle. This review will describe
ecent efforts using chemical synthesis to identify and improve the
target specificity of designed enediynes, and to establish efficient
methods to achieve prodrug activation. Finally, new horizons will
be examined, including the use of post-cycloaromatized enediyne
templates as recognition elements for unique DNA and RNA microenvironments.
[Back to top]
Combinatorial Approaches in Anticancer Drug Discovery: Recent Advances
in Design and Synthesis
Sukanta Bhattacharyya
Combinatorial technology for the generation of molecular
diversity has evolved as an integrated component in accelerated
drug discovery process. During the emerging days of combinatorial
chemistry, solidphase organic synthesis has been the leading strategy
for the production of large libraries for lead discovery. As combinatorial
techniques for the library synthesis has evolved, solution-phase
synthesis of smaller, targeted libraries is gaining attention. Numerous
syntheses of biologically active chemical libraries of small molecules
have been reported during the past decade. This review will focus
only on the recent literature of chemical libraries targeted towards
anticancer properties. The synthesis, chemistry and biological activity
of these libraries as anticancer agents are summarized.
[Back to top]
The Expanding Role of NMR in Rational Drug Design
Rickey P. Hicks and
Daniel A. Nichols
The technology of nuclear magnetic resonance spectroscopy
continues to advance at a rapid pace. The development of NMR based
rapid high throughput screening methods to identify small organic
molecules in complex mixtures that bind to specific protein targets
has proven to be an effective method in lead identification. NMR
coupled to liquid chromatography has opened a new door to the quantitative
and qualitative analysis of complex mixtures including metabolites
extracted from body fluids and extracts containing various natural
products. This review will focus on the following four advances
in NMR technology: 1) pulse-field gradient
(PFG) NMR, 2) SAR (structure activity relationship) by NMR,
3) LC (liquid chromatography) NMR, and 4) application of membrane
models for the study of neuropeptide and host defense peptide conformations.
The information content available to medicinal chemists from each
experiment will be discussed.
[Back to top]
Mass Spectrometry Based Assays for Drug Screening in the Early Phases
of Drug Discovery
Marshall M. Siegel
Electrospray ionization (ESI) and matrix-assisted
laser desorption/ionization (MALDI) mass spectrometric methods useful
for exploratory and early discovery drug screening are reviewed.
All methods described involve studies of non-covalent complexes
between biopolymer receptors and small molecule ligands formed in
the condensed phase. The complexes can be transferred directly into
the gas phase by ESI-MS using gentle experimental conditions. Gas
phase screening applications are illustrated for drug ligand candidates
noncovalently interacting with peptides, proteins, RNA, and DNA.
In the condensed phase, the complexes can be also isolated, denatured
and analyzed by ESI-MS to identify the small molecule ligands. Condensed
phase drug screening examples are illustrated for the ESI-MS ancillary
techniques of affinity chromatography, ultrafiltration, ultracentrifugation,
gel permeation chromatography (GPC), reversed phase-high performance
liquid chromatography (RP-HPLC) and capillary electrophoretic methods.
Solid phase drug screening using MALDI-MS is illustrated for small
molecule ligands bound to MALDI affinity probe tips and to beads.
Since ESI and MALDI principally produce molecular ions, high throughput
screening is achieved by analyzing mass indexed mixtures.
[Back to top]
Recent Advances in PDE4 Inhibitors as Immunoregulators and Anti-inflammatory
Drugs
Catherine Burnouf, Ingrid Devillers and Marie-Pierre Pruniaux
The phosphodiesterases (PDEs) are responsible for
the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate
(cAMP and cGMP, respectively). They are classified into 11 major
families (PDE1-11) and the type 4 phosphodiesterase (PDE4) is a
cAMP-specific enzyme localized in airway smooth muscle cells as
well as in immune and inflammatory cells. The PDE4 activity is associated
with a wide variety of diseases some of which have been related
to an inflammatory state, (e.g. asthma, chronic obstructive pulmonary
disease (COPD), rheumatoid arthritis (RA)) while others have recently
been connected to autoimmune pathology. Therefore, an intense effort
toward the development of PDE4 inhibitors has been generated for
the last decade. Unfortunately, the effects of prototype PDE4 inhibitors
have been compromised by side effects such as nausea and emesis
and the clinical use of those compounds is still limited. Several
companies have focused on the design of a new generation of PDE4
inhibitors dissociating eneficial activity and adverse effects.
This review updates a previous article [1]. It highlights the recent
data of the most advanced clinical candidates, the design and structure
activity relationships of the recent structural series reported
in the literature over the last three and half years, as well as
recent advances in the multiple therapeutic indications of PDE4
inhibitors (a review with more than 500 references).
[Back to top]
Serotonin Reuptake Inhibition: An Update on Current Research Strategies
D. Spinks and G.
Spinks
Selective Serotonin reuptake inhibitors (SSRIs) have
contributed to the major advances in the treatment of depression
and other psychiatric diseases. This review summarises current knowledge
concerning the SSRI class of drugs and discusses the importance
of secondary pharmacology in the mechanism of action and effectiveness
of these drugs. This area of research has shed light on the pharmacological
mechanisms of SSRI therapy and has increased the therapeutic usefulness
of serotonin reuptake inhibition, especially in the area of depression.
Particular attention is given to the emerging importance of the
SSRI ‘plus’ approach: where the serotonin reuptake receptor
inhibition of a drug is supplemented by one or more other receptor
interactions either by the same drug or by a combination therapy.
There are many new emerging SSRI ‘plus’ drugs, which
address the pharmacological and pharmacokinetic issues of current
therapies and these are discussed in detail.
[Back to top]
Emerging b-Amyloid Therapies
for the Treatment of Alzheimer’s Disease
Kelly A. Conway, Ellen W. Baxter, Kevin M. Felsenstein
and Allen B. Reitz
Alzheimer’s Disease (AD) is a progressive neurodegenerative
disorder marked by loss of memory, cognition, and behavioral stability.
AD is defined pathologically by extracellular neuritic plaques comprised
of fibrillar deposits of b-amyloid peptide (Ab)
and neurofibrillary tangles comprised of paired helical filaments
of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase
inhibitors, treat the symptoms but do not modify the progression
of the disease. The etiology of AD is unclear. However, data from
familial AD mutations (FAD) strongly support the “amyloid
cascade hypothesis” of AD, i.e. that neurodegeneration in
AD is initiated by the formation of neurotoxic b-amyloid
(Ab) aggregates; all FAD
mutations increase levels of Ab
peptide or density of Ab
deposits. The likely link between Ab
aggregation and AD pathology emphasizes the need for a better understanding
of the mechanisms of Ab production. This review summarizes current
therapeutic strategies directed at lowering Ab
levels and decreasing levels of toxic Ab
aggregates through (1) inhibition of the processing of amyloid precursor
protein (APP) to Ab peptide,
(2) inhibition, reversal or clearance of Ab
aggregation, (3) cholesterol reduction and (4) Ab
immunization.
[Back to top]
Oxidative Stress in Animal Models of Accelerated Aging, Alzheimer’s
Disease and Huntington’s Disease
D. Allan Butterfield
Oxidative stress in brain is emerging as a potential
causal factor in aging and age-related neurodegenerative disorders.
Brain tissue from living patients is difficult to acquire; hence,
animal models of aging and age-related neurodegenerative disorders,
though not perfect models, have provided tissue to study the role
of oxidative stress in these disorders. In this review, the central
role of oxidative damage in models of accelerated aging (progeria
and Werner’s syndrome) and the age-related neurodegenerative
disorders, Alzheimer’s disease and Huntington’s disease,
will be presented and evaluated. To the extent that the animal models
faithfully mirror their respective disorders, and based on the totality
of the studies, it is apparent that oxidative stress, the excess
of free radicals over the means of scavenging these harmful agents,
may play critical roles in the molecular basis of accelerated aging,
Alzheimer’s disease, and Huntington’s disease.
[Back to top]
Constitutive Activity of Brain Serotonin Receptors: Inverse Agonist
Activity of Antipsychotic Drugs
Anil Purohit, Katharine Herrick-Davis and Milt Teitler
Several lines of evidence indicate that G-protein
coupled receptors (GPCR) may exist in a state that allows a tonic
level of stimulation in vivo (constitutive activity). Several native
forms of GPCR, when expressed in recombinant cell lines, display
significant signal transduction stimulation in the absence of activating
ligand. Many GPCR, including four serotonin receptors, display robust
constitutive activation upon the mutation of a single amino acid,
indicating mutations producing inappropriate constitutive activation
may be etiological factors in diseases. If constitutive activity
of GPCR is as common a phenomenon as some researchers suspect, this
would suggest significant alterations in the classical model of
ligand-receptor interactions. One of the most significant implications
of constitutive activity for pharmacologists and medicinal chemists,
is the possibility of developing drugs that lower the level of constitutive
activity. Such compounds have been termed “inverse agonists”.
These drugs, in theory, would have different physiological effects,
and therefore possibly different therapeutic potential, than classical
competitive receptor antagonists (“neutral antagonists”).
In this review, theoretical issues concerning constitutive activity
in the GPCR family and evidence supporting the existence of constitutively
active GPCR are discussed. Data demonstrating the activation of
human 5-HT2A, 5-HT2C, 5-HT6, and
5-HT7 receptors by single amino acid substitutions are
presented. These studies demonstrate the procedures for producing
and characterizing constitutively active forms of serotonin receptors,
including the demonstration of inverse agonist activity of drugs
on these receptors.
[Back to top]
Physicochemical Profiling (Solubility, Permeability and
Charge State)
Alex Avdeef
About 30% of drug candidate molecules are rejected
due to pharmacokinetic-related failures. When poor pharmaceutical
properties are discovered in development, the costs of bringing
a potent but poorly absorbable molecule to a product stage by "formulation"
can become very high. Fast and reliable in vitro prediction strategies
are needed to filter out problematic molecules at the earliest stages
of discovery. This review will consider recent developments in physicochemical
profiling used to identify candidate molecules with physical properties
related to good oral absorption. Poor solubility and poor permeability
account for many PK failures. FDA's Biopharmaceutics Classification
System (BCS) is an attempt to rationalize the critical components
related to oral absorption. The core idea in the BCS is an in vitro
transport model, centrally embracing permeability and solubility,
with qualifications related to pH and dissolution. The objective
of the BCS is to predict in vivo performance of drug products from
in vitro measurements of permeability and solubility. In principle,
the framework of the BCS could serve the interests of the earliest
stages of discovery research. The BCS can be rationalized by considering
Fick's first law, applied to membranes. When molecules are introduced
on one side of a lipid membrane barrier (e.g., epithelial cell wall)
and no such molecules are on the other side, passive diffusion will
drive the molecules across the membrane. When certain simplifying
assumptions are made, the flux equation in Fick's law reduces simply
to a product of permeability and solubility. Many other measurable
properties are closely related to permeability and solubility. Permeability
(Pe) is a kinetic parameter related to lipophilicity
(as indicated by the partition and distribution coefficients, log
P and log D). Retention (R) of lipophilic molecules by the membrane
(which is related to lipophilicity and may predict PK volumes of
distribution) influences the characterization of permeability. Furthermore,
strong drug interactions with serum proteins can influence permeability. The unstirred water
layer on both sides of the membrane barrier can impose limits on
permeability. Solubility (S) is a thermodynamic parameter, and is
closely related to dissolution, a kinetic parameter. The unstirred
water layer on the surfaces of suspended solids imposes limits on
dissolution. Bile acids effect both solubility and dissolution,
by a micellization effect. For ionizable molecules, pH plays a crucial
role. The charge state that a molecule exhibits at a particular
pH is characterized by the ionization constant (pKa)
of the molecule. Buffers effect pH gradients in the unstirred water
layers, which can dramatically affect both permeability and dissolution
of ionizable molecules. In this review, we will focus on the emerging
instrumental methods for the measurement of the physicochemical
parameters Pe, S, pKa, R, log P, and log D
(and their pH-profiles). These physicochemical profiles can be valuable
tools for the medicinal chemists, aiding in the prediction of in
vivo oral absorption.
[Back to top]
Non-peptide Opioid Receptor Ligands - Recent Advances. Part I -
Agonists
Agnieszka Kaczor and Dariusz Matosiuk
Developments in the domain of non-peptide opioid
receptor agonists, beginning from the first evidence of opiate binding
to definite receptors, are briefly summarized. The recent achievements
are in a more detailed way depicted and discussed. Novel agonists
for each of three opioid receptor basic types (d
(DOR), k (KOR) and m (MOR)) are presented with the special emphasis
on one-type-selective ligands. Such selective or even specific agonists
have been synthesized with a moderate success. Considerably more
serious difficulties concern searching for selective ligands for
opioid receptor subtypes (m1
(MOR1), m2 (MOR2),
d1 (DOR1), d2 (DOR2), k1
(KOR1), k2 (KOR2),
k3 (KOR3)) which may be connected
with the fact that dissimiliarities observed in vivo result from
postbinding processes (signaling).
For the large number of opioid receptor ligands, their
structural diversity and relative easiness of generating them from
combinatorial libraries (not comparable even with that of orphanine
receptors) it is justified to consider the plasticity of opioid
receptors (MOR especially). This remark, in conjunction with the
existence of opioid receptor types and subtypes, may enable to create
new drugs with significantly reduced sideeffects. The above facts
and brand new reports about highly-active opioid agonists possessing
no moieties thought to be essential for agonist activity make the
need of reevaluation of classical opioid receptor pharmacophore
model extremely important.
In general, research results suggest that selective agonists
of opioid receptors can be found both in morphine type of ligands
and new structures like pyrido-acridine derivatives (COMP1) or diphenylmethylpiperazine
derivatives (SNC 80). Better understanding of the structural prerequisites
of the opioid receptors binding domains will certainly lead to even
more potent and more selective ligands in near future.
[Back to top]
Nitric Oxide Therapies in Vascular Diseases
E.M. Kurowska
Endothelial dysfunction defined as the impaired ability
of vascular endothelium to stimulate vasodilation plays a key role
in the development of atherosclerosis and in various pathological
conditions which predispose to atherosclerosis, such as hypercholesterolemia,
hypertension, type 2 diabetes, hyperhomocyst(e)inemia and chronic
renal failure. The major cause of the endothelial dysfunction is
decreased bioavailability of nitric oxide (NO), a potent biological
vasodilator produced in vascular endothelium from Larginine by the
endothelial NO synthase (eNOS). In vascular diseases, the bioavailability
of NO can be impaired by various mechanisms, including decreased
NO production by eNOS, and/or enhanced NO breakdown due to increased
oxidative stress. The deactivation of eNOS is often associated with
elevated plasma levels of its endogenous inhibitor, NG
NG-dimethyl-L-arginine (ADMA). In hypercholesterolemia,
a systemic deficit of NO may also increase the levels of low density
lipoproteins (LDL) by modulating its synthesis and metabolism by
the liver, as suggested by recent in vivo and in vitro studies using
organic NO donors. Therapeutic strategies aiming to reduce the risk
of vascular diseases by increasing bioavailability of NO continue
to be developed. Cholesterollowering drugs, statins, have been shown
to improve endothelial function in patients with hypercholesterolemia
and atherosclerosis. Promising results were also obtained in some,
but not all, vascular diseases after treatment with antioxidant
vitamins (C and E) and after administration of eNOS substrate, L-arginine,
or its cofactor, tetrahydrobiopterin (BH4). Novel strategies,
which may produce beneficial changes in the vascular endothelium,
include the use of natural extracts from plant foods rich in phytochemicals.
[Back to top]
Strategies to Improve Stability and Bioavailability of Peptide Drugs
Celine Adessi and Claudio Soto
Peptides play a major role in a diversity of biological
functions, such as hormones, growth factors and neuropeptides. However,
the development of peptides as therapeutic drugs has been limited
by their poor metabolic stability and their inability to readily
cross membrane barriers such as the intestinal and blood-brain barriers.
The aim of peptide medicinal chemistry is to develop strategies
to overcome these problems. Recent progress in chemical synthesis
and design have resulted in several strategies for producing modified
peptides and mimetics with lower susceptibility to proteolysis and
improved bioavailability, which has increased the probability of
obtaining useful drugs structurally related to parent peptides.
This review describes different experimental approaches to transforming
a peptide into a potential drug and provides examples of the usefulness
of these strategies.
[Back to top]
The Role of Genomics in the Discovery of Novel Antibacterial Targets
Jerry M. Buysse
Complete DNA sequence information has now been obtained
for numerous prokaryotic genomes, defining the entire genetic complement
of these species. The collection of genomic data has provided new
insights into the molecular architecture of bacterial cells, revealing
the basic genetic and metabolic structures that support viability
of the organisms. Genomic information has also revealed new avenues
for inhibition of bacterial growth and viability, expanding the
number of possible drug targets for antibiotic discovery. This review
examines how genomic sciences and experimental tools are applied
to antibacterial target discovery, the necessary first step in the
development of new antibiotic classes. Significant advances have
been realized in the development of functional genomic, comparative
genomic, and proteomic methods for the analysis of completed genomes.
The combination of these methods can be used to systematically parse
the genome and identify targets worthy of inhibitor screens. Two
basic categories of targets emerge from this exercise, comprising
in vitro essential targets required for bacterial viability on synthetic
media and in vivo essential targets required to establish and maintain
infection within a host organism. Current use of genomic information
is focused primarily on a definition of all in vitro essential targets
that satisfy criteria of selectivity, spectrum, and novelty. As
the genomes of additional bacterial pathogens are solved, it will
be possible to select in vivo essential targets common to groups
of select pathogens (e.g., bacterial agents of community acquired
pneumonia) or even pathogen-specific targets. Consideration of host-pathogen
interactions, defined at the level of gene expression for each organism,
might provide novel therapeutic options in the future.
[Back to top]
New Anti-HIV Agents in Preclinical or Clinical Development
Erik De Clercq
Virtually all the compounds that are currently used
(or have been the subject of advanced clinical trials), for the
treatment of HIV infections, belong to one of the following classes:
(i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine,
didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine
and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e. tenofovir
disoproxil fumarate); (ii) nonnucleoside reverse transcriptase inhibitors
(NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and
(iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir,
nelfinavir, amprenavir and lopinavir. In addition to the reverse
transcriptase and protease reaction, various other events in the
HIV replicative cycle can be considered as potential targets for
chemotherapeutic intervention: (i) viral adsorption, through binding
to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates,
polycarboxylates, polyoxometalates, polynucleotides, and negatively
charged albumins); (ii) viral entry, through blockade of the viral
coreceptors CXCR4 [i.e. bicyclam (AMD3100) derivatives] and CCR5
(i.e. TAK-100% derivatives); (iii) virus-cell fusion, through binding
to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral
assembly and disassembly, through NCp7 zinc fingertargeted agents
[2,2’-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)];
(v) proviral DNA integration, through integrase inhibitors such
as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription,
through inhibitors of the transcription (transactivation) process
(flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs
and PIs have been developed that possess, respectively: (i) improved
metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl
pronucleotides by-passing the first phosphorylation step of the
NRTIs), (ii) increased activity [“second” generation
NNRTIs (i.e. TMC-125, DPC-083)] against those HIV strains that are
resistant to the “first” generation NNRTIs, or (iii),
as in the case of PIs, a different, modified peptidic [i.e. azapeptidic
(atazanavir)] or non-peptidic scaffold [i.e. cyclic urea (mozenavir),
4-hydroxy-2-pyrone (tipranavir)]. Non-peptidic PIs may be expected
to inhibit HIV mutant strains that have become resistant to peptidomimetic
PIs.
[Back to top]
DNA Minor Groove Alkylators
William A. Denny
Recent work on a number of different classes of anticancer
agents that alkylate DNA in the minor groove is reviewed. Attachment
of nitrogen mustards to a variety of carrier molecules (intercalators,
polypyrroles, polyimidazoles, bis(benzimidazoles), anilinoquinolinium
salts and polybenzamides) can alter their normal patterns of both
regio- and sequence-selectivity, from reaction primarily at most
guanine N7 sites in the major groove to selected adenine N3 sites
at the 3¢-end of poly(A/T) sequences in the minor groove.
In contrast, similar targeting of pyrrolizidine alkylators by a
variety of carriers has little effect on their patterns of alkylation
(at the 2-amino group of guanine). Finally, the pyrrolobenzodiazepine
and cyclopropaindolone classes of natural products are intrinsic
minor groove alkylating agents. Due to their large DNA binding site
size, minor groove alkylators are highly sequence-selective, with
potential as selective inhibitors of gene expression. However, their
direct clinical use is limited by myelotoxicity, and a major new
application for the more potent compounds is as effectors for prodrugs.
[Back to top]
Applications of Small Molecule Crystallography and the
Cambridge Structural Database in Drug Design
Johan Wouters and
Frederic Ooms
Crystal
structures of small ligands are a source of valuable structural
information helpful in the process of drug design (pharmacophore
model elaborations, 3D QSAR, docking, and de novo design). In particular,
small molecules crystallography can approach ligand-receptor binding
by providing unique structural features both about the conformation
(internal geometry) of the ligand(s) and about the intermolecular
interaction potentially occurring within the active site of a target
(enzyme/receptor). Small molecule crystal structure databases can
also be used in three-dimensional search to identify new drug candidates.
Future development in small molecule crystallography (e.g. powder
diffraction) should also provide original solutions to complex problems
related to polymorphism.
[Back to top]
Compound Optimization in Early and Late Phase Drug Discovery: Acceptable
Pharmacokinetic Properties Utilizing Combined Physicochemical, In
Vitro and In Vivo Screens
Gary W. Caldwell
New chemical entities (NCEs) are abandoned in development
primarily because of insufficient efficacy, safety issues, and for
economic reasons. Since efficacy and safety deficiencies are related
in part to pharmacokinetics (PK), uncovering PK defects as early
in drug discovery as possible would be highly valuable in reducing
NCE failures in preclinical and clinical development. In this review,
a strategy is put forth to integrate drug metabolism/pharmacokinetics
and toxicology functions into drug discovery. Compound optimization
in early and late phase drug discovery is covered emphasizing physicochemical
properties, in vitro absorption, metabolism, and in vivo animal
PK methodologies. The present study also illustrates the idea of
sorting oral bioavailability data into high/intermediate/low categories
based on combining high/low rank-ordered information from physicochemical
properties and in vitro absorption, metabolism, and serum binding
assays. It is shown that by combining the results from solubility,
stability, absorption and metabolism assays the high/intermediate/low
human oral bioavailability for a series of b- blockers can be approximately predicted.
This method has a high sample throughput and should be useful in
rank-ordering the predicted oral bioavailability of large collections
of compounds at the lead optimization step of drug discovery. These
results are useful for selecting compounds for future in vitro-in
vivo correlation modeling or in vivo animal testing. This type of
approach will improve the decision making process of compound selection
in drug discovery.
[Back to top]
DNA-binding of Drugs Used in Medicinal Therapies
G. Bischoff, S. Hoffmann, R. Zhdanov
The interactions of various low-molecular weight
substances with DNA are naturally relevant mechanisms in the cellular
cycle and so also used in medicinal treatment. Depending on the
particular drug structure, DNA-binding modes like groove-binding,
intercalating and/or stacking, give rise to supramolecular assemblies
of the polynucleotides, as well as influence the DNA-protein binding.
In this review, we compare the underlying molecular structures,
including general aspects of DNA sequences, with the benefit in
medicinal treatment. While so far interest in this field had mainly
been devoted to isolated nucleic acid/drug interactions, the present
paper will focus on drug efficiencies generating and influencing
supramolecular organizations and their complex sequence-dependent
structure-activity codes. In particular, the attention will be directed
to stereoelectronic relationships. Spatial enantioselective properties
are discussed in details. As examples, the drug self-assemblies,
as well as the influence of drugs on supramolecular DNA formations
are described. A hypothetical connection between drug-influenced
DNAtoroids and the formation of micronuclei in tissues will be interpreted.
As an important group of medicines a variety of lipids appears,
which could also be bound to chromatin and DNA as an individual
molecules or as lipoproteins. Their upcoming importance on the regulation
of lipid composition in genome, called lipidomics, is briefly described,
too.
[Back to top]
The Contribution of Combinatorial Chemistry to Lead Generation:
An Interim Analysis
Anton E.P. Adang, Pedro H.H. Hermkens
In the process of finding new drug candidates, medicinal
chemists nowadays have a variety of options to choose from, one
is to apply combinatorial chemistry techniques. Since the early
1990’s synthetic and analytical methods as well as new technologies
have been growing rapidly in the area of combinatorial chemistry.
Applying these techniques has resulted in the production of large
numbers of compounds. A trend is observed towards smaller libraries
of compounds with more drug-like properties. An analysis is made
to establish the contribution of combinatorial chemistry in providing
new lead candidates for (pre-)clinical development towards new pharmaceutical
products. Eleven representative examples are given to describe the
impact of combinatorial chemistry on different levels of the lead
discovery and optimization process. Furthermore, reports on combinatorial
chemistry products that are already in (pre) clinical development
were traced back to their source. The interim analysis showed only
limited success of early combinatorial chemistry approaches in terms
of delivering lead candidates. Second generation libraries appear
to be more drug-like and focussed and may result in more compounds
entering clinical development in the future.
[Back to top]
New Paradigms in Drug Design and Discovery
Joseph J. Barchi, Jr. and Nouri Neamati
The new millennium has ushered in an era of science that will revolutionize
a great majority of our daily activities. That revolution is being
experienced by a growing number of the population who are pushing
the average life expectancy closer to the 80-year mark. The primary
reason for this increase is the changes we have made in the last
2-3 decades both in how we live our lives as well as how we treat
our maladies when they arise. The advent of new techniques in diagnostics
and surgery have allowed many to survive debilitating illnesses
when their chances would have been slim only a few years ago. In
addition, several new therapeutic agents have been developed in
the latter part of the 20th century that have improved
our quality of life and increased our overall survival time. New
medicines to treat cardiovascular, degenerative, infectious, and
neoplastic diseases are rapidly being discovered in an effort to
further lengthen our lifetimes. The processes used by academic and
industrial scientist to discover new drugs has recently experienced
a true renaissance with many new and exciting techniques being developed
in only the past 5-10 years. In this review, we will attempt to
outline these latest protocols that chemists and biomedical scientist
are currently employing to rapidly bring new drugs to the clinic.
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