6-AZASTEROIDS - STRUCTURE-ACTIVITY-RELATIONSHIPS FOR INHIBITION OF TYPE-1 AND TYPE-2 HUMAN 5-ALPHA-REDUCTASE AND HUMAN ADRENAL 3-BETA-HYDROXY-DELTA(5)-STEROID DEHYDROGENASE 3-KETO-DELTA(5)-STEROID ISOMERASE

6-Azaandrost-4-en-3-ones were synthesized and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydr oxy-Delta(5)-steroid dehydrogenase/3-keto-Delta(5)-steroid isomerase ( 3BHSD) to explore the structure-activity relationship of this novel se ries in order to optimize potency versus both isozymes of 5AR and sele ctivity versus 3BHSD. Compounds with picomolar IC50's versus human typ e 2 5AR and low nanomolar K-i's versus human type 1 5AR with 100-fold selectivity versus 3BHSD were identified (70). Preliminary in vivo eva luation of some optimal compounds from this series in a chronic castra ted rat model of 5AR inhibitor-induced prostate involution and dog pha rmacokinetic measurements identified a series of 17 diphenylmethyl)car bamoyl]-6-azaandrost-4-en-3-ones (compounds 54, 66, and 67) with good in vivo efficacy and half-life in the dog. Inhibitors with, at the min imum, low nanomolar potency toward both human 5AR's and selectivity ve rsus 3BHSD may show advantages over previously known 5AR inhibitors in the treatment of disease states which depend upon dihydrotestosterone , such as benign prostatic hyperplasia.