Structure-Activity Relationships for Inhibition of Type 1 and 2 Human 5.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

Abstract

A variety of C17 amide-substituted 6-azaandrost-4-en-3-ones were prepared and tested versus human type 1 and 2 steroid 5 alpha-reductase (5AR) and human adrenal 3 beta-hydroxy-delta 5-steroid dehydrogenase/3-keto-delta 5-steroid isomerase (3BHSD) in order to optimize potency versus both isozymes of 5AR and selectivity versus 3BHSD. Two series of potent and selective C17 amides were discovered, 2,5-disubstituted anilides and (arylcycloalkyl)amides. Compounds from each series with picomolar 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 different series of compounds. Evaluation of some optimal compounds from this series in a chronic castrated rat model of 5AR inhibitor induced prostate involution, and pharmacokinetic measurements identified compounds (9, 12, 16, and 29) with good in vivo efficacy and half-life in the dog. An intact rat model of in vivo selectivity for 5AR versus 3BHSD inhibition was also developed. Dual inhibitors of both human 5AR's may show advantages over type 2 selective 5AR inhibitors, such as finasteride (1), in the treatment of disease states which depend upon dihydrotestosterone.

Dihydrotestosterone and the Concept of 5α–Reductase Inhibition in Human Benign Prostatic Hyperplasia

“…Another time–dependent inhibitor of type 2 5α–reductase like finasteride is 17β[N,N(diethyl)carbamyl]–6–aza–androst–4–en–3–one. Unlike finasteride, this 6–aza–steroid is not a time–dependent inhibitor of type 1 5α–reductase [83, 84]. …”

“…Frye et al [83]reported on the optimization of the 6–aza–androst–4–en–3–ones for potent dual inhibition of type 1 and 2 enzymes and selectivity versus 3β–hydroxysteroid dehydrogenase/3–oxo–steroid isomerase (3βHSD), a crucial enzyme in steroid biosynthesis. Substitution at C–17 was found to influence 3βHSD structure–activity relationship most strongly, and a conformational model was developed which accounts for the observed potency trends.…”

The Mce3R Regulon Is Required for 6-Azasteroid Potentiation of Anti-TB Drug Activity

“…17β-Carbomethoxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one, 1, was synthesized as reported (16)(17)(18) and converted to 17β-Carboxy-6-t-butoxycarbonyl-6-azaandrost-4-en-3-one as described (17). Compounds were assessed to be greater than 95% pure by 1 H-NMR spectroscopy.…”

“…6-azasteroids (Scheme 1) were developed during the Glaxo-Wellcome 5α-reductase inhibitor program for treatment of benign prostatic hyperplasia, and subsequently abandoned in favor of the 4-azasteroid framework (15)(16)(17)(18). Several members of the 6-azasteroid family were found to be orally bioavailable in rats and/or dogs and to have low in vivo toxicity (16).…”

“…Several members of the 6-azasteroid family were found to be orally bioavailable in rats and/or dogs and to have low in vivo toxicity (16). Due to the pharmacokinetic properties of 6-azasteroids and their structural similarity to cholesterol, we exploited this scaffold for screening as inhibitors of Mtb cholesterol metabolism.…”