QSAR study of HMGR inhibitors: 7-(heteroaryl)-3,5-dihydroxy-6-heptenoic (-heptanoic) acids.
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) inhibitory activity of pyridine- and pyrimidine-substituted 3,5-dihydroxyhept-6(E)-enoic acids and 7-(1H-pyrrol-3-yl)-substituted-3,5-dihydroxyhept-6(E)-enoic (-heptanoic) acids was quantitatively analysed using hydrophobicity, molar refractivity, electronic and Verloop's steric parameters. The results obtained were comparable to the earlier findings of 7-(aryl/biphenyl)-3,5-dihydroxy-6-heptenoic (-heptanoic) acids. The R'4-substituent of the aryl substituent of heteroaryl moiety was found to influence the inhibitory activity through its steric and electronic properties, and the equations confirm that substituents with minimum steric bulk, positive polar and negative resonance constants lead to better inhibitory activity. The changes in the heteroaryl moiety of the inhibitors did not correlate with the activity. Probably, the heteroaryl moiety of the inhibitors may be serving as a skeletal framework to hold the surrounding hydrophobic substituents.
Prabhakar
Y S
YS
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow, India.
D000818:Animals; D002478:Cells, Cultured; D006538:Heptanoic Acids / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008956:Models, Chemical; D051381:Rats; D013329:Structure-Activity Relationship
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors