title: 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.
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.
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Terasawa
authors.forename: H
authors.initials: H
authors.lastname: Hagihara
authors.forename: Y
authors.initials: Y
authors.lastname: Sakuma
authors.forename: N
authors.initials: N
authors.lastname: Ishibe
authors.forename: M
authors.initials: M
authors.lastname: Sawada
authors.forename: H
authors.initials: H
authors.lastname: Takasugi
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000284:Administration, Oral; D000302:Adrenal Cortex / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000924:Anticholesteremic Agents; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D014508:Urea; D002784:Cholesterol; C112873:FR 186054; D002785:Sterol O-Acyltransferase