De Sign and Synthesis of 1,2,4‐Oxadiazole Derivatives as Non‐Steroidal 5α‐Reductase Inhibitors

Abstract

The pur pose of this study was to syn the size com pounds in which the 1,2,4-oxadiazole moi ety re placed the am ide bond of ONO3805 and to eval u ate its 5 -reductase in hib i tory ac tiv ity as a po ten tial be nign prostatic hy per pla sia ther a peu tic tar get. Four 1,2,4-oxadiazole de riv a tives, 1, 2, 8, and 20, were eval u ated in vi tro against 5 -reductase of rat liver microsome. The pre pared 1 and 2 pos sessed sim i lar bind ing af fin ity (Ki) to that of ONO3805. There fore, the use of 1,2,4-oxadiazole ring as sur ro gate of the am ide bond in ONO3805 has a suc cess ful re sult in this study. It leads not only to en hance chem i cal sta bil ity but also to main tain mean ing ful in hib i tory ac tiv ity. The bu tyric acid moi ety of these in hib i tors is con sid ered to play an im por tant role in mimicing the phos pho ric acid por tion of coenzyme-NADPH in in ter act ing with the ac tive site of 5 -reductase. IN TRO DUC TIONSte roid 5 -reductase is a mem brane-associated enzyme, which cat a lyzes the re duc tion of tes tos ter one to the bio log i cally more ac tive dihydrotestosterone (DHT) in the pres ence of NADPH.1 El e vated DHT has been im pli cated as a caus ative fac tor of skin dis or ders and be nign pros tatic hy perpla sia (BPH). 2 There fore, in hi bi tion of 5 -reductase is an attrac tive tar get for ther a peu tic in ter ven tion in dis or ders as soci ated with el e vated lev els of DHT such as BPH, 3,4 acne, 5 male pat tern bald ness, 6 and hirsutism. 7 A num ber of 5 -reductase in hib i tors have been re ported, in clud ing both steroidal 8 and nonsteroidal in hib i tors. 9 Starting our re search pro gram to find a new 5 -reductase in hib i tor, we fo cused our at ten tion on the de vel op ment of novel nonsteroidal compounds, es pe cially ONO3805. Ac cord ing to the bioiso s terism, 10 some re search groups have suc cess fully re placed the es ter or am ide group of bi o log i cally ac tive com pounds by an 1,2,4-oxadiazole moi ety to im prove in vivo ef fi cacy. 11 The intramolecular acid cat a lyzed the hy dro ly sis of the am ide bond 1 2,13 even though the hy dro ly sis ex hib its a half-life of 7 years un der neu tral con di tions and at room tem per a ture. 14 In ad di tion, we found that the am ide bond of ONO3805 was partially cleaved in a DMSO-d6 so lu tion at 37 o C in four months.Re place ment of the am ide bond with a 1,2,4-oxadiazole ring for in creas ing hydrolytic re sis tance, 1 5 met a bolic sta bil ity, and im prov ing pharmacokinetic per for mance 16 has been reported. Herein, de riv a tives with 1,2,4-oxadiazole sur ro gate of the am ide bond in ONO3805 as po ten tial 5 -reductase inhib i tors were de signed and syn the sized (Fig. 1). RE SULTS AND DIS CUS SIONThe syn the sis of tar get com pound 1 is il lus trated in