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Inhibitors of acyl-coA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N- (heteroaryl-substituted benzyl)-N'-arylureas

Journal of Medicinal Chemistry, ISSN: 0022-2623, Vol: 41, Issue: 13, Page: 2390-2410
1998
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Article Description

A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar = pyrazol-3- yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (At), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED = 0.046 mg/kg dosed via the diet, ED = 0.44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.

Bibliographic Details

Akira Tanaka; Takeshi Terasawa; Hisashi Takasugi; Hiroyuki Hagihara; Noriko Ishibe; Masae Sawada; Hirokazu Tanaka; Yuri Sakuma

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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