Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity

被引：116

作者：

Lin, Linus S. ^{[1
]}

Lanza, Thomas J., Jr.

Jewell, James P.

Liu, Ping

Shah, Shrenik K.

Qi, Hongbo

Tong, Xinchun

Wang, Junying

Xu, Suoyu S.

Fong, Tung M.

Shen, Chun-Pyn

Lao, Julie

Xiao, Jing Chen

Shearman, Lauren P.

Stribling, D. Sloan

Rosko, Kimberly

Strack, Alison

Marsh, Donald J.

Feng, Yue

Kumar, Sanjeev

Samuel, Koppara

Yin, Wenji

Van der Ploeg, Lex H. T.

Goulet, Mark T.

Hagmann, William K.

机构：

[1] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Metab Disorders, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 26期

关键词：

D O I：

10.1021/jm060996+

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

引用

页码：7584 / 7587

页数：4

共 23 条

[1]

Burns D. H., 2005, Heterocyclic Radiolabeled Cannabinoid-1 Receptor Modulators, Patent No. [2005009479, WO 2005009479 A1]

[2] New bicyclic cannabinoid receptor-1 (CB1-R) antagonists [J].

Carpino, PA ;

Griffith, DA ;

Sakya, S ;

Dow, RL ;

Black, SC ;

Hadcock, JR ;

Iredale, PA ;

Scott, DO ;

Fichtner, MW ;

Rose, CR ;

Day, R ;

Dibrino, J ;

Butler, M ;

DeBartolo, DB ;

Dutcher, D ;

Gautreau, D ;

Lizano, JS ;

O'Connor, RE ;

Sands, MA ;

Kelly-Sullivan, D ;

Ward, KM .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (03) :731-736

[3] A NEW METHOD FOR DIRECTED CONVERSION OF PHENOXY GROUPING INTO A VARIETY OF CYCLIC POLYFUNCTIONAL SYSTEMS [J].

COREY, EJ ;

BARCZA, S ;

KLOTMANN, G .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1969, 91 (17) :4782-&

[4] Synthesis of functionalized 1,8-naphthyridinones and their evaluation as novel, orally active CB1 receptor inverse agonists [J].

Debenham, JS ;

Madsen-Duggan, CB ;

Walsh, TF ;

Wang, JY ;

Tong, XC ;

Doss, GA ;

Lao, J ;

Fong, TM ;

Schaeffer, MT ;

Xiao, JC ;

Huang, CRRC ;

Shen, CP ;

Feng, Y ;

Marsh, DJ ;

Stribling, DS ;

Shearman, LP ;

Strack, AM ;

MacIntyre, DE ;

Van der Ploeg, LHT ;

Goulet, MT .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (03) :681-685

[5] Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development [J].

Evans, DC ;

Watt, AP ;

Nicoll-Griffith, DA ;

Baillie, TA .

CHEMICAL RESEARCH IN TOXICOLOGY, 2004, 17 (01) :3-16

[6]

FELDER CC, 1995, MOL PHARMACOL, V48, P443

[7]

FONG TM, UNPUB J PHARM EXP TH

[8] Stereoselective synthesis of J-104,118 and J-104,123, novel potent inhibitors of squalene synthase [J].

Iwasawa, Y ;

Shibata, J ;

Nonoshita, K ;

Arai, S ;

Masaki, H ;

Tomimoto, K .

TETRAHEDRON, 1996, 52 (44) :13881-13894

[9] Medicinal chemistry strategies to CB1 cannabinoid receptor antagonists [J].

Lange, JHM ;

Kruse, CG .

DRUG DISCOVERY TODAY, 2005, 10 (10) :693-702

[10] Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB1 cannabinoid receptor antagonists [J].

Lange, JHM ;

Coolen, HKAC ;

van Stuivenberg, HH ;

Dijksman, JAR ;

Herremans, AHJ ;

Ronken, E ;

Keizer, HG ;

Tipker, K ;

McCreary, AC ;

Veerman, W ;

Wals, HC ;

Stork, B ;

Verveer, PC ;

den Hartog, AP ;

de Jong, NMJ ;

Adolfs, TJP ;

Hoogendoorn, J ;

Kruse, CG .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (03) :627-643

← 1 2 3 →