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Structure-activity relationship of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl)propoxy] phenyl]-N'-pentylurea and analogues. Novel potent inhibitors of acyl-CoA:cholesterol O-acyltransferase with antiatherosclerotic activity.

Abstract：

:We have discovered N-butyl-N'-[2-(dimethylamino)-6-[3-(4-phenyl-1H- imidazol-1-yl)propoxy]phenyl]urea (4), a novel, potent, and systemically bioavailable inhibitor of ACAT (acylCoA:cholesterol O-acyltransferase). The structure-activity relationships (SARs) of this lead compound 4 were investigated by systematic modification of four regions in the molecule. The compounds prepared in this study were tested for in vitro inhibitory activity toward both aortic and intestinal ACATs, and selected compounds were further tested for in vivo hypocholesterolemic activity. The studies not only resulted in the discovery of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl) propoxy]phenyl]-N'-pentylurea (24), with potent activity and moderate plasma level after oral administration, but also revealed the SAR in each modified region. Four compounds (4, 13, 14, 24) were further selected for testing of in vivo antiatherosclerotic activity; 4, 13, and 24 reduced atherosclerotic plaque development to 38-45% of the control value in terms of area, while 14 did not have a significant antiatherosclerotic effect.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kimura T,Takase Y,Hayashi K,Tanaka H,Ohtsuka I,Saeki T,Kogushi M,Yamada T,Fujimori T,Saitou I

doi

10.1021/jm00063a013

subject

Has Abstract,Author List Incomplete

pub_date

1993-05-28 00:00:00

pages

1630-40

issue

11

eissn

0022-2623

issn

1520-4804

journal_volume

36

pub_type

杂志文章

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