Abstract:
:A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was beta to the urea moiety and not alpha, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (-47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
O'Brien PM,Sliskovic DR,Blankley CJ,Roth BD,Wilson MW,Hamelehle KL,Krause BR,Stanfield RLdoi
10.1021/jm00038a010subject
Has Abstractpub_date
1994-06-10 00:00:00pages
1810-22issue
12eissn
0022-2623issn
1520-4804journal_volume
37pub_type
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