Azasteroids as inhibitors of rat prostatic 5 alpha-reductase.
A series of A-ring heterocyclic steroids has been prepared and tested for inhibition of rat prostatic steroid 5 alpha-reductase in vitro. Strikingly high inhibitory activity was found with a group of 17 beta-substituted 4-methyl-4-aza-5 alpha-androstan-3-ones. These compounds were prepared from 3-keto-delta 4-precursors by oxidative (O3 or NaIO4-KMnO4) A-ring cleavage followed, in turn, by ring closure with an amine and hydrogenation over platinum catalyst. Other A-ring azasteroids were made by Beckmann rearrangement of oximes of 2-oxo-A-nor, 3-oxo- and 4-oxo-5 alpha-androstanes. An A-nor-2-oxo-3-azasteroid was prepared by oxidative decarbonylation of a precursor 2,3-dioxo-4-azasteroid with m-chloroperbenzoic acid. A-ring modifications of the 4-azasteroids included delta 1-unsaturation, 2- and 4-substituents, and 3-carbonyl replacements. Side chains at the 17-position were varied with an emphasis on carboxylate derivatives (salts, esters, and amides).
D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001378:Azasteroids / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D009904:Optical Rotation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011467:Prostate / Q000201:enzymology*; D051381:Rats; D013260:Steroids, Heterocyclic / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D007202:Indicators and Reagents; D013260:Steroids, Heterocyclic; D010088:Oxidoreductases