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
A TanakaH Tanaka

Abstract

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, Ar1 = 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 (Ar3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 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.

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Citations

Jul 31, 2008·Journal of Medicinal Chemistry·Sanjeev KumarAlexander J Muller
Apr 28, 2011·Acta Crystallographica. Section E, Structure Reports Online·Roman LytvynVasyl Kinzhybalo
Aug 10, 2000·Drugs·P H Chong, B S Bachenheimer
Oct 23, 2004·Bioorganic & Medicinal Chemistry·Yeong Woo JoEung Chil Choi
Dec 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hong DaiJian Shi
Sep 1, 2005·Chemistry : a European Journal·Gebhard HaberhauerFrank Rominger
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Mar 3, 2005·Antiviral Chemistry & Chemotherapy·Mario SechiNouri Neamati
Jul 29, 2019·Bioorganic & Medicinal Chemistry·Daniel J BurkettMartin St Maurice
Jun 19, 2009·Journal of Medicinal Chemistry·Rong-Jian LuConnie Sexton
Jun 1, 2001·Journal of Medicinal Chemistry·Z P ZhuangH F Kung
Apr 21, 2001·The Journal of Organic Chemistry·N ZhangB Wu
May 13, 2004·Chemical Reviews·Rafael ChinchillaMiguel Yus

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