Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles

C. Anne Higley; Richard G. Wilde; Thomas P. Maduskuie; Alexander L. Johnson; Pennio Pennev; Jeffrey T. Billheimer; Candy S. Robinson; Peter J. Gillies; Ruth R. Wexler

doi:10.1021/jm00047a009

Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles

C. Anne Higley, Richard G. Wilde, Thomas P. Maduskuie, Alexander L. Johnson, Pennio Pennev, Jeffrey T. Billheimer, Candy S. Robinson, Peter J. Gillies, Ruth R. Wexler

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N′-{2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2-yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC₅₀ = 10 nM and possessing potent antihypercholesterolemic activity in vivo.

Original language	English (US)
Pages (from-to)	3511-3522
Number of pages	12
Journal	Journal of medicinal chemistry
Volume	37
Issue number	21
DOIs	https://doi.org/10.1021/jm00047a009
State	Published - Oct 1 1994
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm00047a009

Cite this

Higley, C. A., Wilde, R. G., Maduskuie, T. P., Johnson, A. L., Pennev, P., Billheimer, J. T., Robinson, C. S., Gillies, P. J., & Wexler, R. R. (1994). Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles. Journal of medicinal chemistry, 37(21), 3511-3522. https://doi.org/10.1021/jm00047a009

@article{4bce3afe977e4c4f9ffe8bbec370af52,

title = "Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles",

abstract = "A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N′-{2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2-yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.",

author = "Higley, {C. Anne} and Wilde, {Richard G.} and Maduskuie, {Thomas P.} and Johnson, {Alexander L.} and Pennio Pennev and Billheimer, {Jeffrey T.} and Robinson, {Candy S.} and Gillies, {Peter J.} and Wexler, {Ruth R.}",

year = "1994",

month = oct,

day = "1",

doi = "10.1021/jm00047a009",

language = "English (US)",

volume = "37",

pages = "3511--3522",

journal = "Journal of medicinal chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "21",

}

Higley, CA, Wilde, RG, Maduskuie, TP, Johnson, AL, Pennev, P, Billheimer, JT, Robinson, CS, Gillies, PJ & Wexler, RR 1994, 'Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles', Journal of medicinal chemistry, vol. 37, no. 21, pp. 3511-3522. https://doi.org/10.1021/jm00047a009

TY - JOUR

T1 - Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors

T2 - Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles

AU - Higley, C. Anne

AU - Wilde, Richard G.

AU - Maduskuie, Thomas P.

AU - Johnson, Alexander L.

AU - Pennev, Pennio

AU - Billheimer, Jeffrey T.

AU - Robinson, Candy S.

AU - Gillies, Peter J.

AU - Wexler, Ruth R.

PY - 1994/10/1

Y1 - 1994/10/1

N2 - A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N′-{2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2-yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.

AB - A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N′-{2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2-yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo.

UR - http://www.scopus.com/inward/record.url?scp=0027985805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027985805&partnerID=8YFLogxK

U2 - 10.1021/jm00047a009

DO - 10.1021/jm00047a009

M3 - Article

C2 - 7932580

AN - SCOPUS:0027985805

SN - 0022-2623

VL - 37

SP - 3511

EP - 3522

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 21

ER -

Acyl CoA:Cholesterol Acyltransferase (ACAT) Inhibitors: Synthesis and Structure-Activity Relationship Studies of a New Series of Trisubstituted Imidazoles

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this