Inhibition of pyridine-nucleotide-dependent enzymes by pyrazoles. Synthesis and enzymology of a novel A-ring pyrazole steroid.
A novel A-ring pyrazole steroid, 2,3-bisaza-A-nor-1,5(10)-estradien-17 beta-ol (3), was synthesized as a potential inhibitor of steroidal NAD(P)H-dependent oxidoreductases. Compound 3 proved to be a potent inhibitor of 3(17)beta-hydroxysteroid dehydrogenase (from P. testosteroni) exhibiting a Ki of 90 +/- 20 nM. The activities of 3 alpha,20 beta-hydroxysteroid dehydrogenase (from S. hydrogenans), steroid-5 alpha-reductase (from rat prostate), and 3 alpha-hydroxysteroid dehydrogenase (from rat liver) were unaffected by pyrazole 3. Dead end inhibition studies indicate an ordered binding of cofactor prior to substrate or pyrazole inhibitor.
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D001665:Binding Sites; D003349:Cortisone Reductase / Q000037:antagonists & inhibitors; D004963:Estrenes / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D009243:NAD / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D011467:Prostate / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D013260:Steroids, Heterocyclic / Q000494:pharmacology*
D058891:5-alpha Reductase Inhibitors; D001378:Azasteroids; D004963:Estrenes; D013260:Steroids, Heterocyclic; D009243:NAD; C055390:2,3-bisaza-A-nor-1,5(10)-estradien-17-ol; D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D003349:Cortisone Reductase; D009247:NADH, NADPH Oxidoreductases