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

J Med Chem. 1998 Jun 18;41(13):2390-410. doi: 10.1021/jm9800853.

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.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Adrenal Cortex / drug effects
  • Adrenal Cortex / pathology
  • Animals
  • Anticholesteremic Agents / chemical synthesis
  • Anticholesteremic Agents / chemistry
  • Anticholesteremic Agents / pharmacology
  • Anticholesteremic Agents / toxicity
  • Cholesterol / blood
  • Cholesterol, Dietary / administration & dosage
  • Dogs
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • In Vitro Techniques
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / ultrastructure
  • Intestine, Small / drug effects
  • Intestine, Small / enzymology
  • Intestine, Small / ultrastructure
  • Microsomes / drug effects
  • Microsomes / enzymology
  • Necrosis
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology
  • Pyrazoles / toxicity
  • Rabbits
  • Rats
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / chemistry
  • Urea / pharmacology
  • Urea / toxicity

Substances

  • Anticholesteremic Agents
  • Cholesterol, Dietary
  • Enzyme Inhibitors
  • Pyrazoles
  • Urea
  • Cholesterol
  • FR 186054
  • Sterol O-Acyltransferase