The purpose of this study was to synthesize compounds in which the 1,2,4-oxadiazole moiety replaced the amide bond of ONO3805 and to evaluate its 5α-reductase inhibitory activity as a potential benign prostatic hyperplasia therapeutic target. Four 1,2,4-oxadiazole derivatives, 1,2,8, and 20, were evaluated in vitro against 5α-reductase of rat liver microsome. The prepared 1 and 2 possessed similar binding affinity (Ki) to that of ONO3805. Therefore, the use of 1,2,4-oxadiazole ring as surrogate of the amide bond in ONO3805 has a successful result in this study. It leads not only to enhance chemical stability but also to maintain meaningful inhibitory activity. The butyric acid moiety of these inhibitors is considered to play an important role in mimicing the phosphoric acid portion of coenzyme-NADPH in interacting with the active site of 5α-reductase.
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