HMG-COA REDUCTASE INHIBITORS - DESIGN, SYNTHESIS, AND BIOLOGICAL-ACTIVITY OF TETRAHYDROINDAZOLE-SUBSTITUTED 3,5-DIHYDROXY-6-HEPTENOIC ACID SODIUM-SALTS

Compounds comprising a series of rahydro-2H-indazol-3-yl]-3,5-dihydrox y-6-heptenoic acid sodium salts (18) were synthesized and tested for t heir ability to inhibit HMG-CoA reductase in a partially purified enzy me preparation and cholesterol biosynthesis from acetate in cultured H EP-G2 cells. Changing the size of the saturated ring of the tetrahydro indazole nucleus did not improve potency, but incorporation of substit uents at the 7-position resulted in up to 1700-fold improvement in inh ibitory potency. Structure-activity studies revealed that the most pot ent compounds possess a substituted benzyl group at the 7-position, wi th a preference for steric bulk at the para position of the benzene ri ng. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approxima tely 3-fold more potent than lovastatin sodium salt (2). The most pote nt cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.0 78 muM) is slightly less potent than 2 (sodium salt). Molecular modeli ng studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.