Hypocholesterolemic activity of some novel azetidin-2-ones in diet and diabetes induced hypercholesterolemia in rats.
Some novel substituted azetidin-2-ones (5-8) were synthesized via [2 + 2] cycloaddition reactions of imines and ketenes and evaluated for their ability to prevent diet and diabetes induced hypercholesterolemia. The test compounds 5a and 7a significantly (p < 0.01) inhibited the rise in serum total cholesterol induced by peanut oil (5.5%), cholesterol (1.5%) and cholic acid (0.5%) diet in both acute and chronic models in a dose dependent manner. Compound 5a also raised the high density lipoprotein-cholesterol levels in chronic diet models by peanut oil (5.5%), cholesterol (1.5%) and cholic acid (0.5%). In a diabetes induced model of hypercholesterolemia, the test compounds were evaluated for preventing diabetes-induced hypercholesterolemia (protocol 1) as well as for lowering post diabetic hypercholesterolemia (protocol 2). Test compounds 5a-g and 7a-d significantly (p < 0.05) reduced serum total cholesterol with a greater reduction in protocol 1 as compared with protocol 2. Based on SAR studies, the substituents that favor hypocholesterolemic activity around the azetidin-2-one nucleus are discussed and a possible mechanism of action is proposed on the basis of their differential effects in two protocols of diabetes-induced hypercholesterolemia.
Goel
R K
RK
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Thind
J S
JS
Bal
C S
CS
Mahajan
M P
MP
Kulkarni
S K
SK
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001384:Azetidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D004032:Diet; D005260:Female; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000209:etiology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D001384:Azetidines; C095487:1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone; D002785:Sterol O-Acyltransferase