Discovery of pyrazine carboxamide CB1 antagonists: The introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series

被引：30

作者：

Ellsworth, Bruce A. ^{[1
]}

Wang, Ying ^{[1
]}

Zhu, Yeheng ^{[1
]}

Pendri, Annapurna ^{[1
]}

Gerritz, Samuel W. ^{[1
]}

Sun, Chongqing ^{[1
]}

Carlson, Kenneth E. ^{[1
]}

Kang, Liya ^{[1
]}

Baska, Rose A. ^{[1
]}

Yang, Yifan ^{[1
]}

Huang, Qi ^{[1
]}

Burford, Neil T. ^{[1
]}

Cullen, Mary Jane ^{[1
]}

Johnghar, Susan ^{[1
]}

Behnia, Kamelia ^{[1
]}

Pelleymounter, Mary Ann ^{[1
]}

Washburn, William N. ^{[1
]}

Ewing, William R. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 14期

关键词：

cannabinoid; CBI; GPCR; obesity; pyrazine; ADME; hypophagia; antagonist;

D O I：

10.1016/j.bmcl.2007.04.087

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose. (C) 2007 Elsevier Ltd. All rights reserved.

引用

页码：3978 / 3982

页数：5

共 32 条

[1] CB1 cannabinoid receptor antagonists for treatment of obesity and prevention of comorbid metabolic disorders [J].

Antel, Jochen ;

Gregory, Peter C. ;

Nordheim, Ulrich .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (14) :4008-4016

[2] Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases [J].

Bellocchio, Luigi ;

Mancini, Giacomo ;

Vicennati, Valentina ;

Pasquali, Renato ;

Pagotto, Uberto .

CURRENT OPINION IN PHARMACOLOGY, 2006, 6 (06) :586-591

[3]

BOSTROM J, 2007, IN PRESS BIOORG MED

[4] Obesity: The disease [J].

Bray, George A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (14) :4001-4007

[5] 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

[6] Appetite suppression and weight loss after the cannabinoid antagonist SR141716 [J].

Colombo, G ;

Agabio, R ;

Diaz, G ;

Lobina, C ;

Reali, R ;

Gessa, GL .

LIFE SCIENCES, 1998, 63 (08) :PL113-PL117

[7]

Cota D, 2003, J CLIN INVEST, V112, P423, DOI [10.1172/JCI200317725, 10.1172/JCI17725]

[8] 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

[9] The endocannabinoid system and its therapeutic exploitation [J].

Di Marzo, V ;

Bifulco, M ;

De Petrocellis, L .

NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (09) :771-784

[10] Lessons learned from marketed and investigational prodrugs [J].

Ettmayer, P ;

Amidon, GL ;

Clement, B ;

Testa, B .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (10) :2393-2404

← 1 2 3 4 →