1. Academic Validation
  2. Discovery of potent and orally bioavailable 17β-hydroxysteroid dehydrogenase type 3 inhibitors

Discovery of potent and orally bioavailable 17β-hydroxysteroid dehydrogenase type 3 inhibitors

  • Bioorg Med Chem. 2012 May 15;20(10):3242-54. doi: 10.1016/j.bmc.2012.03.052.
Koichiro Harada 1 Hideki Kubo Jun Abe Mari Haneta Arnel Conception Shinichi Inoue Satoshi Okada Kazuhiko Nishioka
Affiliations

Affiliation

  • 1 Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka 554-8558, Japan. haradak@sc.sumitomo-chem.co.jp
Abstract

We have previously reported the discovery of a new class of potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17β-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17β-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at CA 10% level of control over 4h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate Cancer.

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