Synthesis of 21,21-difluoro-3 beta-hydroxy-20-methylpregna-5,20-diene and 5,16,20-triene as potential inhibitors of steroid C17(20) lyase.
Novel 21,21-difluorovinyl steroids, designed as difluorinated C20(21) enol mimics of pregnenolone, were targeted as potential mechanism-based inhibitors of C17(20) lyase, a crucial enzyme in the biosynthesis of testosterone. Addition of (difluoromethyl)diphenylphosphine oxide reagent to 17-acetyl steroids was the approach chosen for the construction of these compounds. Of particular interest were the abnormal Wittig products which formed during attempted preparation of the triene 9. The target difluoroolefin 3 was found to be a moderately potent, time-dependent inhibitor of the enzyme.
Weintraub
Philip M
PM
Aventis Pharmaceuticals; Rte 202-206, PO Box 6800, Bridgewater, NJ 08807-0800, USA. philip.weintraub@aventis.com
Holland
Amy K
AK
Gates
Cynthia A
CA
Moore
William R
WR
Resvick
Robert J
RJ
Bey
Philippe
P
Peet
Norton P
NP
D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D011284:Pregnenolone / Q000737:chemistry* / Q000494:pharmacology*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013259:Steroids, Fluorinated / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology; D013997:Time Factors
D004791:Enzyme Inhibitors; D013259:Steroids, Fluorinated; D011284:Pregnenolone; D013254:Steroid 17-alpha-Hydroxylase