The discovery of 4-{l-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]- 3thienyl}carbonyl)amino]cyclopropyl}benzoic acid (MK-2894), a potent and selective prostaglandin e2 subtype 4 receptor antagonist

Journal of Medicinal Chemistry

Volumn 53, Issue 5, 2010, Pages 2227-2238

  Blouin, Marc ^a   Han, Yongxin ^a   Burch, Jason ^a   Farand, Julie ^a   Mellon, Christophe ^a   Gaudreault, Mireille ^a   Wrona, Mark ^a   Lévesque, Jean François ^a   Denis, Danielle ^a   Mathieu, Marie Claude ^a   Stocco, Rino ^a   Vigneault, Erika ^a   Therien, Alex ^a   Clark, Patsy ^a   Rowland, Steve ^a   Xu, Daigen ^a   o'Neill, Gary ^a   Ducharme, Yves ^a   Friesen, Rick ^a  

^a MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

4 [1 ((2,5 DIMETHYL 4 (4 TRIFLUOROMETHYLBENZYL) 3 THIENYLCARBONYL) AMINO) CYCLOPROPYL] BENZOIC ACID; CJ 042794; CYCLOOXYGENASE 2 INHIBITOR; INDOMETACIN; MK 2894; PROSTAGLANDIN RECEPTOR BLOCKING AGENT; ROFECOXIB; UNCLASSIFIED DRUG; ANALGESIC AGENT; BENZOIC ACID DERIVATIVE; CYCLOPROPANE DERIVATIVE; PROSTAGLANDIN E RECEPTOR; THIOPHENE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTHRITIS; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TOLERABILITY; EXPERIMENTAL DOG; EXPERIMENTAL MONKEY; FEMALE; HUMAN; HUMAN CELL; HYPERALGESIA; INFLAMMATION; MALE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; PAIN; RAT; STRUCTURE ACTIVITY RELATION; SWELLING; ANIMAL; CHEMISTRY; DRUG ANTAGONISM; HALF LIFE TIME; METABOLISM; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; SPRAGUE DAWLEY RAT; SYNTHESIS;

ANALGESICS; ANIMALS; BENZOIC ACIDS; CYCLOPROPANES; HALF-LIFE; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MALE; PAIN; PROSTAGLANDIN ANTAGONISTS; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, PROSTAGLANDIN E; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES;

EID: 77949421409     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm901771h     Document Type: Article

References (36)

1. Flower, R. J. The Development of COX-2 Inhibitors. Nat. Rev. Drug Discovery 2003, 2,179-191.
2. Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Bosi Ferraz, M.; Hawkey, C. J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer, T. J. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. N. Engl. J. Med. 2000, 343, 1520-1528.
3. (a) Solomon, S. D.; McMurray, J. J. V.; Pfeffer, M. A.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W. F.; Zauber, A.; Hawk, E.; Bertagnolli, M. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention. N. Engl. J. Med. 2005, 352, 1071-1080.
4. (b) Nussmeier, N. A.; Whelton, A. A.; Brown, M. T.; Langford, R. M.; Hoeft, A.; Parlow, J. L.; Boyce, S. W.; Verburg, K. M. Complications of the COX-2 Inhibitors Parecoxib and Valdecoxib after Cardiac Surgery. N. Engl. J. Med. 2005, 352,10811091.
5. (c) Bresalier, R. S.; Sandler, R. S.; Quan, H.; Bolognese, J. A.; Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton, D.; Lanas, A.; Konstram, M. A.; Baron, J. A. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. N. Engl. J. Med. 2005, 352, 1092-1102.
6. (a) McAdam, B. F.; Catella-Lawson, F.; Mardini, I. A.; Kapor, S.; Lawson, J. A.; FitzGerald, G. A. Systemic Biosynthesis of Prostacyclin by Cyclooxygenase (COX)-2: The Human Pharmacology of a Selective Inhibitor of COX-2. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 272-277.
7. (b) FitzGerald, G. A.; Patrono, C. The Coxibs, Selective Inhibitors of Cyclooxygenase-2. N. Engl. J. Med. 2001, 345, 433-442.
8. For a recent review see: (c) Funk, C. D.; FitzGerald, G. A. COX-2 Inhibitors and Cardiovascular Risk. J. Cardiovasc. Pharmacol. 2007, 50, 470-479.
9. McCoy, J. M.; Wicks, J. R.; Audoly, L. P. The Role of Prostaglandin E2 Receptors in the Pathogenesis of Rheumatoid Arthritis. J. Clin. Invest. 2002,110, 651-658.
10. 4 signaling both mediate joint inflammation in mouse collagen-induced arthritis. J. Exp. Med. 2006, 203, 325-335.
11. 2 Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity. J. Pharmacol. Exp. Ther. 2006, 319, 1096-1103.
12. Clark, P.; Rowland, S. E.; Denis, D.; Mathieu, M.-C.; Stocco, R.; Poirier, H.; Burch, J.; Han, Y.; Audoly, L.; Therien, A. G.; Xu, D. MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4g]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. Pharmacol. Exp. Ther. 2008, 325, 425-434.
13. Gpollone, F.; Fazia, M. L.; Iezzi, A.; Cuccurullo, C.; De Cesare, D.; Ucchino, S.; Spigonardo, F.; Marchetti, A.; Buttitta, F; Paloscia, L.; Mascellanti, M.; Cuccurullo, F.; Mezzetti, A. Association Between Prostaglandin E Receptor Subtype EP4 Overexpression and Unstable Phenotype in Atherosclerotic Plaques in Human. Arterioscler. Thromb. Vase. Biol. 2005, 25,1925-1931.
14. (a) Ma, X.; Kundu, N.; Rifat, S.; Walser, T.; Fulton, A. M. Prostaglandin E Receptor EP4 Antagonism Inhibits Breast Cancer Metastasis. Cancer Res. 2006, 66, 2923-2927.
15. (b) Chell, S. D.; Witherden, I. R.; Dobson, R. R.; Moorghen, M.; Herman, A. A.; Qualtrough, D.; Williams, A. C.; Paraskeva, C. Increased EP4 Receptor Expression in Colorectal Cancer Progression Promotes Cell Growth and Anchorage Independence. Cancer Res. 2006, 66, 3106-3113.
16. (c) Yang, L.; Huang, Y.; Porta, R.; Yanagisawa, K.; Gonzalez, A.; Segi, E.; Johnson, D. H.; Narumiya, S.; Carbone, D. P. Host and Direct Antitumor Effects and Profound Reduction in Tumor Metastasis with Selective EP4 Receptor Antagonism. Cancer Res. 2006, 66, 96659672.
17. 2 Stimulates Human Lung Carcinoma Cell Growth through Induction of Integrin-Linked Kinase: The Involvement of EP4 and Spl. Cancer Res. 2009, 69, 896-904.
18. Maubach, K. A.; Davis, R. J.; Clark, D. E.; Fenton, G.; Lockey, P. M.; Clark, K. L.; Oxford, A. W.; Hagan, R. M.; Routledge, C.; Coleman, R. A. BGC20-1531, a Novel, Potent and Selective Prostanoid EP4 Receptor Antagonist: A Putative New Treatment for Migraine Headache. Br. J. Pharmacol. 2009, 156, 316-327.
19. 4 Receptor. J. Biol. Chem. 2009, 284, 18493-18502.
20. 4 Receptor. Bioorg. Med. Chem. Lett. 2008, 18, 2048-2054.
21. The elimination half-life of M1 in rat and dog was estimated to be > 24 h. When compound 2 was dosed orally at 20 mg/kg/day for 5 days in rats, M1 levels at 24 h increased from 1.4 μM after the first dose to 4.6 μM after the last dose. When 2 was dosed in dogs at 4 mg/kg/day for two weeks, M1 levels at 24 h increased from 1.3 μM after the first dose to 13.7 μM after the last dose.
22. Han, Y.; Giroux, A.; Lépine, C.; Laliberté, F.; Huang, Z.; Perrier, H.; Bayly, C.; Young, R. N. Solid Phase Parallel Synthesis of Highly Substituted Thiophene Derivatives and Identification of Novel PDE-4 Inhibitors. Tetrahedron 1999, 55, 11669.
23. 2 Antagonists. Patent Application WO 2005/021508 A1, March 10, 2005.
24. Skramstad, J.; Lunde, A.; Hope, H.; Bjørnsatd, V.; Froyen, P. Chlorinated Thiophenes. Part 2. Trihalogenated Hydroxythiophenes; Preparation, Reactions and Tautomeric Properties. J. Chem. Soc., Perkin Trans. 2 2000, 1453-1458.
25. Bertus, P.; Szymoniac, J. A Direct Synthesis of 1-Aryl- and 1Alkenylcyclopropylamines from Aryl and Alkenyl Nitriles. J. Org. Chem. 2003, 68, 7133-7136.
26. Jütten, P.; Schumann, W.; Härtl, A.; Dahse, H.-M.; Gräfe, U. Thiosemicarbazones of Formyl Benzoic Acids as Novel Potent Inhibitors of Estrone Sulfatase. J. Med. Chem. 2007, 50, 36613666.
27. 4 Receptor Antagonists. J. Med. Chem. 2005, 48, 3103-3106.
28. (b) Takeuchi, K.; Tanaka, A.; Kato, S.; Aihara, E.; Amagase, K. Effect of (S)-4-(l-(5-Chloro-2-(4-fluorophenoxy)benzamido)ethyl) Benzoic Acid (CJ-42794), a Selective Antagonist of Prostaglandin E Receptor Subtype 4, on Ulcerogenic and Healing Responses in Rat Gastrointestinal Mucosa. J. Pharmacol. Exp. Ther. 2007, 322, 903-912.
29. 4 Receptor Antagonist, CJ-042,794, in Rat Models of Pain and Inflammation. Eur. J. Pharmacol. 2008, 580, 116-121.
30. 4 Receptor Antagonist. Life Sci. 2008, 82, 116-131.
31. Abramovitz, M.; Adam, M.; Boie, Y.; Carrière, M.-C.; Denis, D.; Godbout, C.; Lamontagne, S.; Rochette, C.; Sawyer, N.; Tremblay, N. M.; Belley, M.; Gallant, M.; Dufresne, C.; Gareau, Y.; Ruel, R.; Juteau, H.; Labelle, M.; Ouimet, N.; Metters, K. M. The Utilization of Recombinant Prostanoid Receptors to Determine the Affinities and Selectivities of Protaglandins and Related Analogs. Biochim. Biophys. Acta 2000, 1483, 285-293.
32. 2 and IFN-y: Implications for Rheumatoid Arthritis. Eur. J. Immunol. 2008, 55, 1900-1912.
33. Boyce, S.; Chan, C.-C.; Gordon, R.; Li, C.-S.; Rodger, I. W.; Webb, J. K.; Rupniak, N. M. J.; Hill, R. G. L-745,337: A Selective Inhibitor of Cyclooxygenase-2 Elicits Antinociception But Not Gastric Ulceration in Rats. Neuropharmacology 1994, 33, 1609.
34. Rowland, S. E.; Clark, P.; Gordon, R.; Mullen, A. K.; Guay, J.; Dufresne, L.; Brideau, C.; Côté, B.; Ducharme, Y.; Mancini, J.; Chan, C.-C.; Audoly, L.; Xu, D. Pharmacological Characterization of a Selective COX-2 Inhibitor MF-tricyclic, [3-(3,4Difluorophenyl)-4-(methylsulfonyl)phenyl)-2-(5H)- furanone], in Multiple Preclinical Species. Eur. J. Pharmacol. 2007, 560, 216-224.
35. Chan, C.-C.; Boyce, S.; Brideau, C.; Charleson, S.; Cromlish, W.; Éthier, D.; Evans, J.; Ford-Hutchinson, A. W.; Forrest, M. J.; Gauthier, J. Y.; Gordon, R.; Gresser, M.; Guay, J.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Léger, S.; Mancini, J.; O'Neill, G. P.; Ouellet, M.; Patrick, D.; Percival, M. D.; Perrier, H.; Prasit, P.; Rodger, I.; Tagari, P.; Thérien, M.; Vickers, P.; Visco, D.; Wang, Z.; Webb, J.; Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R.; Riendeau, D. Rofecoxib [Vioxx, MK-0966; 4-(4'-Methylsulfonylphenyl)-3-phenyl-2-(5//)-furanone]: A Potent and Orally Active Cyclooxygenase-2 Inhibitor. Pharmacological and Biochemical Profiles. J. Pharmacol. Exp. Ther. 1999, 290, 551-560.
36. Cook, M. J.; Jafari-Fini, A. Phthalocyanine-Related Macrocycles: Cross Cyclotetramerisation Products from 3,4-Dicyanothiophenes, 2,3-Dicyanothiophene and 3,6-Dialkylphthalonitriles. Tetrahedron 2000, 56, 4085-4094