Tanaka A, Terasawa T, Hagihara H, Sakuma Y, Ishibe N, Sawada M, Takasugi H, Tanaka H
Medicinal Chemistry Research Laboratories, Medicinal Biology Research Laboratories, and New Drug Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532, Japan.
J Med Chem. 1998 Jun 18;41(13):2390-410. doi: 10.1021/jm9800853.
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.
已经制备了一系列由2和3表示的N-烷基-N-（杂芳基取代的苄基）-N'-芳基脲及其相关衍生物，并评估了它们在体外抑制酰基辅酶A：胆固醇O-酰基转移酶以及在体内降低胆固醇喂养大鼠血浆胆固醇水平的能力。在这些新型化合物中，3型系列表现更优。该三取代脲的N-苄基上的吡唑-3-基（即3，Ar1 =吡唑-3-基）被确定为具有良好生物活性的杂芳环。通过优化与N-烷基（R）和N-芳基（Ar3）的组合，化合物3aq（FR186054）被鉴定为一种新型的口服有效的ACAT抑制剂，它在体外表现出强大的ACAT抑制活性（兔肠微粒体IC50 = 99 nM），并且在胆固醇喂养的大鼠中具有出色的降胆固醇作用，无论给药方式如何（通过饮食给药的ED50 = 0.046 mg/kg，在PEG400载体中通过灌胃给药的ED50 = 0.44 mg/kg）。此外，一项毒理学研究表明，当以10 mg/kg的单剂量口服给药时，化合物3aq对犬的肾上腺无毒。
