Thiadiazoles as new inhibitors of diacylglycerol acyltransferase type 1

被引：27

作者：

Mougenot, Patrick ^{[1
]}

Namane, Claudie ^{[1
]}

Fett, Eykmar ^{[1
]}

Camy, Florence ^{[1
]}

Dadji-Faihun, Rommel ^{[1
]}

Langot, Gwladys ^{[1
]}

Monseau, Catherine ^{[1
]}

Onofri, Benedicte ^{[1
]}

Pacquet, Francois ^{[1
]}

Pascal, Cecile ^{[1
]}

Crespin, Olivier ^{[1
]}

Ben-Hassine, Majdi ^{[1
]}

Ragot, Jean-Luc ^{[1
]}

Van-Pham, Thao ^{[1
]}

Philippo, Christophe ^{[1
]}

Chatelain-Egger, Florence ^{[1
]}

Peron, Philippe ^{[1
]}

Le Bail, Jean-Christophe ^{[1
]}

Guillot, Etienne ^{[1
]}

Chamiot-Clerc, Philippe ^{[1
]}

Chabanaud, Marie-Aude ^{[1
]}

Pruniaux, Marie-Pierre ^{[1
]}

Schmidt, Friedemann ^{[2
]}

Venier, Olivier ^{[1
]}

Nicolai, Eric ^{[1
]}

Viviani, Fabrice ^{[1
]}

机构：

[1] Sanofi Aventis R&D, Early Candidate Unit, F-91385 Chilly Mazarin, France

[2] Sanofi Aventis Deutschland GmbH, Lead Generat Candidate Realizat Design & Informat, D-65926 Frankfurt, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 07期

关键词：

Diacylglycerol acyltransferase type 1; DGAT-1; inhibitors; Triacylglycerides inhibition; Thiadiazole; Pharmacodynamic in vivo assay; POTENT; OBESITY; MICE; DISCOVERY; DGAT-1;

D O I：

10.1016/j.bmcl.2012.02.006

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel class of DGAT1 inhibitors containing a thiadiazole core has been discovered. Chemical optimization lead to inhibitors of human DGAT1 with an appropriate ADME profile and that show in vivo activity in target tissues. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2497 / 2502

页数：6

共 25 条

[1]

[Anonymous], PROGR ACD9 WAS US PR

[2]

Birch AM, 2010, CURR OPIN DRUG DISC, V13, P489

[3]

Bovy P.R., 2003, [No title captured], Patent No. [WO2003/099772, 2003099772]

[4] Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis [J].

Cases, S ;

Smith, SJ ;

Zheng, YW ;

Myers, HM ;

Lear, SR ;

Sande, E ;

Novak, S ;

Collins, C ;

Welch, CB ;

Lusis, AJ ;

Erickson, SK ;

Farese, RV .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (22) :13018-13023

[5] Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members [J].

Cases, S ;

Stone, SJ ;

Zhou, P ;

Yen, E ;

Tow, B ;

Lardizabal, KD ;

Voelker, T ;

Farese, RV .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :38870-38876

[6]

Chen HC, 2002, J CLIN INVEST, V109, P1049, DOI [10.1172/JCI200214672, 10.1172/JCI0214672]

[7]

Clark M., 1990, TETRAHEDRON COMPUT M, V3, P47, DOI [DOI 10.1016/0898-5529(90)90120-W, 10.1016/0898-5529(90)90120-W]

[8] COMPARATIVE MOLECULAR-FIELD ANALYSIS (COMFA) .1. EFFECT OF SHAPE ON BINDING OF STEROIDS TO CARRIER PROTEINS [J].

CRAMER, RD ;

PATTERSON, DE ;

BUNCE, JD .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (18) :5959-5967

[9] Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino[2,3-d]pyrimidine core [J].

Dow, Robert L. ;

Andrews, Melissa ;

Aspnes, Gary E. ;

Balan, Gayatri ;

Gibbs, E. Michael ;

Guzman-Perez, Angel ;

Karki, Kapil ;

LaPerle, Jennifer L. ;

Li, Jian-Cheng ;

Litchfield, John ;

Munchhof, Michael J. ;

Perreault, Christian ;

Patel, Leena .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (20) :6122-6125

[10] Discovery of PF-04620110, a Potent, Selective, and Orally Bioavailable Inhibitor of DGAT-1 [J].

Dow, Robert L. ;

Li, Jian-Cheng ;

Pence, Michael P. ;

Gibbs, E. Michael ;

LaPerle, Jennifer L. ;

Litchfield, John ;

Piotrowski, David W. ;

Munchhof, Michael J. ;

Manion, Tara B. ;

Zavadoski, William J. ;

Walker, Gregory S. ;

McPherson, R. Kirk ;

Tapley, Susan ;

Sugarman, Eliot ;

Guzman-Perez, Angel ;

DaSilva-Jardine, Paul .

ACS MEDICINAL CHEMISTRY LETTERS, 2011, 2 (05) :407-412

← 1 2 3 →