STRUCTURE-ACTIVITY-RELATIONSHIPS FOR INHIBITION OF TYPE-1 AND 2 HUMAN5-ALPHA-REDUCTASE AND HUMAN ADRENAL 3-BETA-HYDROXY-DELTA(5)-STEROID DEHYDROGENASE 3-KETO-DELTA(5)-STEROID ISOMERASE BY 6-AZAANDROST-4-EN-3-ONES - OPTIMIZATION OF THE C17 SUBSTITUENT/

A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepa red and tested versus human type 1 and 2 steroid 5 alpha-reductase (5A R) and human adrenal 3 beta-hydroxy-Delta 5-steroid dehydrogenase/3-ke to-Delta 5-steroid isomerase (3BHSD) in order to optimize potency vers us both isozymes of 5AR and selectivity versus 3BHSD. Two series of po tent and selective C17 amides were discovered, 2,5-disubstituted anili des and (arylcycloalkyl)amides. Compounds from each series with picomo lar IC50's versus human type 2 5AR and low nanomolar to picomolar IC50 's versus human type 1 5AR possessing 100-500-fold selectivity versus 3BHSD were identified. A conformational model to predict 3BHSD potency was developed which could rationalize 3BHSD potency within three diff erent series of compounds. Evaluation of some optimal compounds from t his series in a chronic castrated rat model of 5AR inhibitor induced p rostate involution, and pharmacokinetic measurements identified compou nds (9, 12, 16, and 29) with good in vivo efficacy and half-life in th e dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's ma y show advantages over type 2 selective 5AR inhibitors, such as finast eride (1), in the treatment of disease states which depend upon dihydr otestosterone.