title: Discovery of potent and orally bioavailable 17β-hydroxysteroid dehydrogenase type 3 inhibitors.
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.
authors.affiliation: 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
authors.forename: Koichiro
authors.initials: K
authors.lastname: Harada
authors.forename: Hideki
authors.initials: H
authors.lastname: Kubo
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.forename: Mari
authors.initials: M
authors.lastname: Haneta
authors.forename: Arnel
authors.initials: A
authors.lastname: Conception
authors.forename: Shinichi
authors.initials: S
authors.lastname: Inoue
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishioka
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004952:Esters; D010710:Phosphates; D013739:Testosterone; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3