N-imidazolylchroman-4-ones, N-imidazolyl-1-tetralones, and their alcohols as hypolipemic agents raising high-density lipoproteins.
A series of 3-(1-imidazolyl)chroman-4-ones and 2-(1-imidazolyl)-1-tetralones II, some of their alcohols, and some related compounds were synthesized and tested for hypolipidemic activity. Compounds II, bearing appropriate lipophilic substituents on the phenyl ring, strongly reduced total serum cholesterol while raising high-density lipoprotein cholesterol in diet-induced hypercholesterolemic rats. 3-(1-Imidazolyl)chroman-4-ols and 2-(1-imidazolyl)-1-tetralols corresponding to II retained the hypolipidemic activity while removal of the carbonyl or hydroxy group adjacent to imidazole gave inactive compounds. Although many of the active compounds significantly increased liver weight, the one studied as a model, 6-chloro-3-(1-imidazolyl)-2,3-dihydro-4H-1-benzopyran-4-one (5), caused no peroxisome proliferation. Compound 5 and the corresponding alcohol 40, as representatives of the ketone and alcohol series, showed significant hypolipidemic activity in normolipemic rats. Some of the compounds assayed in cholesterol biosynthesis inhibited acetate incorporation but none inhibited HMG-CoA reductase. 5-Bromo-6-hydroxy-2-(1-imidazolyl)-3,4-dihydro-1(2H)-naphthalenone (38), which showed strong activity but caused little hepatomegaly in the rat, was chosen for further pharmacological evaluation.
D000438:Alcohols / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D004790:Enzyme Induction / Q000187:drug effects; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000138:chemical synthesis*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D066298:In Vitro Techniques; D008075:Lipoproteins, HDL / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects; D008862:Microsomes, Liver / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D000438:Alcohols; D000960:Hypolipidemic Agents; D007093:Imidazoles; D008075:Lipoproteins, HDL; D011743:Pyrimidines; C016908:pirinixil; D002784:Cholesterol