The Discovery of 4-{1-[({2,5-Dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic Acid (MK-2894), A Potent and Selective Prostaglandin E2 Subtype 4 Receptor Antagonist

被引：23

作者：

Blouin, Marc ^{[1
]}

Han, Yongxin ^{[1
]}

Burch, Jason ^{[1
]}

Farand, Julie ^{[1
]}

Mellon, Christophe ^{[1
]}

Gaudreault, Mireille ^{[2
]}

Wrona, Mark ^{[2
]}

Levesque, Jean-Francois ^{[2
]}

Denis, Danielle ^{[4
]}

Mathieu, Marie-Claude ^{[4
]}

Stocco, Rino ^{[4
]}

Vigneault, Erika ^{[4
]}

Therien, Alex ^{[4
]}

Clark, Patsy ^{[3
]}

Rowland, Steve ^{[3
]}

Xu, Daigen ^{[3
]}

O'Neill, Gary ^{[4
]}

Ducharme, Yves ^{[1
]}

Friesen, Rick ^{[1
]}

机构：

[1] Merck Frosst Canada Ltd, Merck Frosst Ctr Therapeut Res, Dept Med Chem, Kirkland, PQ H9H 3L1, Canada

[2] Merck Frosst Canada Ltd, Merck Frosst Ctr Therapeut Res, Dept DMPK, Kirkland, PQ H9H 3L1, Canada

[3] Merck Frosst Canada Ltd, Merck Frosst Ctr Therapeut Res, Dept In Vivo Sci, Kirkland, PQ H9H 3L1, Canada

[4] Merck Frosst Canada Ltd, Merck Frosst Ctr Therapeut Res, Dept In Vitro Sci, Kirkland, PQ H9H 3L1, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 05期

关键词：

PHARMACOLOGICAL CHARACTERIZATION; JOINT INFLAMMATION; COX-2; INHIBITORS; CELL-GROWTH; EP4; PAIN; PROSTACYCLIN; DERIVATIVES; ROFECOXIB; MODELS;

D O I：

10.1021/jm901771h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery of highly potent and selective second generation EP4 antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.

引用

页码：2227 / 2238

页数：12

共 35 条

[1] The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs [J].

Abramovitz, M ;

Adam, M ;

Boie, Y ;

Carrière, MC ;

Denis, D ;

Godbout, C ;

Lamontagne, S ;

Rochette, C ;

Sawyer, N ;

Tremblay, NM ;

Belley, M ;

Gallant, M ;

Dufresne, C ;

Gareau, Y ;

Ruel, R ;

Juteau, H ;

Labelle, M ;

Ouimet, N ;

Metters, KM .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2000, 1483 (02) :285-293

[2] A direct synthesis of 1-aryl- and 1-alkenylcyclopropylamines from aryl and alkenyl nitriles [J].

Bertus, P ;

Szymoniak, J .

JOURNAL OF ORGANIC CHEMISTRY, 2003, 68 (18) :7133-7136

[3] Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. [J].

Bombardier, C ;

Laine, L ;

Reicin, A ;

Shapiro, D ;

Burgos-Vargas, R ;

Davis, B ;

Day, R ;

Ferraz, MB ;

Hawkey, CJ ;

Hochberg, MC ;

Kvien, TK ;

Schnitzer, TJ ;

Weaver, A .

NEW ENGLAND JOURNAL OF MEDICINE, 2000, 343 (21) :1520-1528

[4] L-745,337 - A SELECTIVE INHIBITOR OF CYCLOOXYGENASE-2 ELICITS ANTINOCICEPTION BUT NOT GASTRIC-ULCERATION IN RATS [J].

BOYCE, S ;

CHAN, CC ;

GORDON, R ;

LI, CS ;

RODGER, IW ;

WEBB, JK ;

RUPNIAK, NMJ ;

HILL, RG .

NEUROPHARMACOLOGY, 1994, 33 (12) :1609-1611

[5] Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial [J].

Bresalier, RS ;

Sandler, RS ;

Quan, H ;

Bolognese, JA ;

Oxenius, B ;

Horgan, K ;

Lines, C ;

Riddell, R ;

Morton, D ;

Lanas, A ;

Konstam, MA ;

Baron, JA .

NEW ENGLAND JOURNAL OF MEDICINE, 2005, 352 (11) :1092-1102

[6] Structure-activity relationships and pharmacokinetic parameters of quinoline acylsulfonamides as potent and selective antagonists of the EP4 receptor [J].

Burch, Jason D. ;

Belley, Michel ;

Fortin, Rejean ;

Deschenes, Denis ;

Girard, Mario ;

Colucci, John ;

Farand, Julie ;

Therien, Alex G. ;

Mathieu, Marie-Claude ;

Denis, Danielle ;

Vigneault, Erika ;

Levesque, Jean-Francois ;

Gagne, Sebastien ;

Wrona, Mark ;

Xu, Diagen ;

Clark, Patsy ;

Rowland, Steve ;

Han, Yongxin .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (06) :2048-2054

[7]

Chan CC, 1999, J PHARMACOL EXP THER, V290, P551

[8] Increased EP4 receptor expression in colorectal cancer progression promotes cell growth and anchorage independence [J].

Chell, SD ;

Witherden, AR ;

Dobson, RR ;

Moorghen, M ;

Herman, AA ;

Qualtrough, D ;

Williams, AC ;

Paraskeva, C .

CANCER RESEARCH, 2006, 66 (06) :3106-3113

[9] Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human [J].

Cipollone, F ;

Fazia, ML ;

Iezzi, A ;

Cuccurullo, C ;

De Cesare, D ;

Ucchino, S ;

Spigonardo, F ;

Marchetti, A ;

Buttitta, F ;

Paloscia, L ;

Mascellanti, M ;

Cuccurullo, F ;

Mezzetti, A .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (09) :1925-1931

[10] MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}2-(2-methoxyphenyl)acetamide], a selective E prostanoid receptor 4 antagonist, relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis [J].

Clark, Patsy ;

Rowland, Steven E. ;

Denis, Danielle ;

Mathieu, Marie-Claude ;

Stocco, Rino ;

Poirier, Hugo ;

Burch, Jason ;

Han, Yongxin ;

Audoly, Laurent ;

Therien, Alex G. ;

Xu, Daigen .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 325 (02) :425-434

← 1 2 3 4 →