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.
MeSH terms
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Administration, Oral
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Adrenal Cortex / drug effects
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Adrenal Cortex / pathology
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Animals
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Anticholesteremic Agents / chemical synthesis
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Anticholesteremic Agents / chemistry
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Anticholesteremic Agents / pharmacology
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Anticholesteremic Agents / toxicity
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Cholesterol / blood
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Cholesterol, Dietary / administration & dosage
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Dogs
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Drug Design
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / toxicity
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In Vitro Techniques
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / enzymology
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Intestinal Mucosa / ultrastructure
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Intestine, Small / drug effects
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Intestine, Small / enzymology
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Intestine, Small / ultrastructure
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Microsomes / drug effects
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Microsomes / enzymology
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Necrosis
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyrazoles / toxicity
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Rabbits
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Rats
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Sterol O-Acyltransferase / antagonists & inhibitors*
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis
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Urea / chemistry
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Urea / pharmacology
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Urea / toxicity
Substances
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Anticholesteremic Agents
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Cholesterol, Dietary
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Enzyme Inhibitors
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Pyrazoles
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Urea
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Cholesterol
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FR 186054
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Sterol O-Acyltransferase