4-Aza-3-oxo-5.alpha.-androst-1-ene-17.beta.-N-arylcarboxamides as Dual Inhibitors of Human Type 1 and Type 2 Steroid 5.alpha.-Reductases. Dramatic Effect of N-Aryl Substituents on Type 1 and Type 2 5.alpha.-Reductase Inhibitory Potency

Journal of Medicinal Chemistry
1995.0

Abstract

Steroid 5α-reductase type 1 and type 2 are tissue-specifically expressed in humans and mediate the conversion of testosterone to dihydrotestosterone (DHT), a more potent androgen involved in benign prostatic hyperplasia (BPH), acne, hirsutism, and male pattern baldness. Current inhibitors include type 2-selective agents (finasteride, epristeride) and type 1-selective agents (MK-386, LY 191704), but finasteride does not effectively inhibit type 1, leaving residual DHT. Dual inhibitors targeting both isozymes may more effectively lower DHT and improve efficacy. Following the previously reported dual inhibitor 6-azasteroid 5, this study describes the synthesis and in vitro 5α-reductase activity of 4-aza-3-oxo-5α-androst-1-ene-17β-N-arylcarboxamides. Some compounds are potent inhibitors of both human type 1 and type 2 isozymes. Structure-activity relationship analysis revealed that alkylation of the anilide amide nitrogen drastically reduced inhibitory activity against both isozymes; ortho-substituents like F or CF3 on the aryl ring enhanced type 1 potency; polar groups (e.g., OH, NH2) on the aryl ring generally decreased type 1 activity. Five compounds (7, 9a, 9d, 13b, 14a) were slow-binding inhibitors of both isozymes. In a dog model of prostate shrinkage, compound 7 (L-697,818), a potent dual inhibitor, effectively reduced prostate volume and prostatic DHT, similar to finasteride.

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