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Synthesis and Biological Evaluation of Spiro-δ-lactones as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 2 (17β-HSD2)  8(5): Pp. 406 - 421 Kuiying Xu, Marie Wetzel, Rolf W. Hartmann and Sandrine Marchais-Oberwinkler [View Abstract] [Open Access Plus]

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyzes the oxidation of the potent estradiol (E2) to the less active estrogen estrone (E1). Inhibitors of this enzyme should maintain the local level of E2 in bone tissue when the E2 concentration in the circulation drops and therefore might be useful for the treatment of osteoporosis. In this work, novel non-steroidal spiro-δ-lactone compounds designed as 17β-HSD2 inhibitors were synthesized and their physicochemical and biological properties were investigated. These new spiro-δ-lactones are not sufficiently stable for further development and show low inhibition of the enzyme.

Phenylpyazoleanilides as Potent Inhibitor of IL-15 Dependent T Cell Proliferation. Part 2: Discovery of a New Drug Candidate, Y-320  5(4): Pp. 292 - 296 Hiroyuki Ushio, Seigo Ishibuchi, Kunitomo Adachi, Kouichi Oshita and Kenji Chiba [View Abstract] [Open Access Plus]

Through the optimization of the active metabolite 2 of the piperidine derivative 1, we discovered a potent new drug candidate for the treatment of RA, Y-320 that inhibits T cell activation induced by IL-15 and shows a therapeutic effect on collagen-induced arthritis in DBA/1J mice. Design and structure-activity relationships are described.

Selective Androgen Receptor Modulators Antagonize Apolipoprotein E4-Induced Cognitive Impairments  5(4): Pp. 271 - 276 Summer Acevedo, Luis Gardell, Stefania Risso Bradley, Fabrice Piu and Jacob Raber [View Abstract] [Open Access Plus]

While tissue specific effects of selective androgen receptor modulators (SARMs) outside the brain have been reported, little is known about brain specific SARMs. Here we show that SARMs upregulate androgen receptor levels in brain following castration and antagonize impairments in hippocampus-dependent novel location recognition and spatial memory retention in apoE4 female mice. Together with the reduced androgen levels in aged men and women and the beneficial effects of androgens on brain function and pathology in Alzheimers disease-related models, these data support the therapeutic potential of SARMs for age-related cognitive decline and Alzheimers disease.

Phenylpyazoleanilides as a Potent Inhibitor of IL-15 Dependent T Cell Proliferation. Part 1: A New Class of Orally Available Immunomodulators  5(2): Pp. 111 - 115 Hiroyuki Ushio, Seigo Ishibuchi, Kunitomo Adachi, Kouichi Oshita and Kenji Chiba [View Abstract] [Open Access Plus]

In research for a new immunomodulator, we discoverd a novel hydroxypiperidine derivative 9h which was a potent inhibitor of IL-15induced T cell activation. Further modification of 9h gave a potent and orally active agent 10 which was effective in a mouse CIA model.