Antagonists of the EP3 receptor for prostaglandin e2 are novel antiplatelet agents that do not prolong bleeding

ACS Chemical Biology

Volumn 4, Issue 2, 2009, Pages 115-126

  Singh, Jasbir ^a   Zeller, Wayne ^a   Zhou, Nian ^a   Hategen, Georgeta ^a   Mishra, Rama ^a   Polozov, Alex ^a   Yu, Peng ^a   Onua, Emmanuel ^a   Zhang, Jun ^a   Zembower, David ^a   Kiselyov, Alex ^a   Ramírez, José L ^b   Sigthorsson, Gudmundur ^b   Bjornsson, Jon Mar ^b   Thorsteinsdottir, Margret ^b   Andresson, Thorkell ^b   Bjarnadottir, Maria ^b   Magnusson, Olafur ^b   Fabre, Jean Etienne ^c   Stefansson, Kari ^b   Gurney, Mark E ^a,b   more..

^a DeCODE Chemistry & Biostructures   (United States)

^b DECODE GENETICS   (Iceland)

^c INSTITUT DE GÉNÉTIQUE ET DE BIOLOGIE MOLÉCULAIRE ET CELLULAIRE   (France)

Author keywords

[No Author keywords available]

Indexed keywords

CLOPIDOGREL; DG 041; PROSTAGLANDIN E2; PROSTAGLANDIN E3; PROSTAGLANDIN RECEPTOR BLOCKING AGENT; PURINERGIC P2Y12 RECEPTOR; UNCLASSIFIED DRUG; 3 (1 ((2,4 DICHLOROPHENYL)METHYL) 5 FLUORO 3 METHYL 1H INDOL 7 YL) N ((4,5 DICHLORO 2 THIENYL)SULFONYL) 2 PROPENAMIDE; 3-(1-((2,4-DICHLOROPHENYL)METHYL)-5-FLUORO-3-METHYL-1H-INDOL-7-YL)-N-((4,5-DICHLORO-2-THIENYL)SULFONYL)-2-PROPENAMIDE; ACRYLAMIDE DERIVATIVE; ANTITHROMBOCYTIC AGENT; DRUG DERIVATIVE; PROSTAGLANDIN E RECEPTOR; PROSTAGLANDIN EP3 RECEPTOR; PURINERGIC P2 RECEPTOR; SULFONE; TICLOPIDINE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BLEEDING TIME; CLINICAL TRIAL; DRUG ACTIVITY; DRUG FORMULATION; DRUG HALF LIFE; DRUG INHIBITION; FEMALE; HUMAN; HUMAN CELL; MALE; NONHUMAN; NORMAL HUMAN; PRIORITY JOURNAL; RAT; STRUCTURE ACTIVITY RELATION; THROMBOCYTE AGGREGATION; ANIMAL; BLEEDING; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; METABOLISM; THROMBOSIS;

RATTUS;

ACRYLAMIDES; ANIMALS; DINOPROSTONE; FEMALE; HEMORRHAGE; HUMANS; MALE; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PROSTAGLANDIN ANTAGONISTS; RATS; RECEPTORS, PROSTAGLANDIN E; RECEPTORS, PURINERGIC P2; SULFONES; THROMBOSIS; TICLOPIDINE;

EID: 65249093133     PISSN: 15548929     EISSN: None     Source Type: Journal    
DOI: 10.1021/cb8002094     Document Type: Article

References (31)

1. Ross, R. (1999) Atherosclerosis-an inflammatory disease, N. Engl. J. Med. 340,115-126.
2. The Physicians' Health Study: aspirin forthe primary prevention of myocardial infarction, (1988) N. Engl. J. Med. 318,924-926.
3. Collaborative overview of randomised trials of antiplatelet therapy-I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration, (1994) Br. Med.J. 308,81-106.
4. Bhatt, D., Hirsch, A., Ringleb, P., Hacke, W., and Topol, E. (2000) Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators, Am. Heart 1.140, 67-73.
5. Wiviott, S., Braunwald, E., McCabe, C., Montalescot, G., Ruzyllo, W., Gottlieb, S., Neumann, F., Ardissino, D., De Servi, S., Murphy, S., Riesmeyer, J., Weerakkody, G., Gibson, M., and Antman, E. M. (2007) The TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes, N. Engl. J. Med. 357, 2001-2015.
6. Bhatt, D. (2007) Intensifying platelet inhibition-navigating between Scylla and Charybdis, N. Engl. J. Med. 357, 2078-2081.
7. Funk, C. D. (2001) Prostaglandins and leukotrienes: advances in ei- cosanoid biology, Science 294,1871-1875.
8. Grosser, T, Fries, S, and FitzGerald, G A. (2006) Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities, J. Clin. Invest. 116,4-15.
9. Cipollone, F., Cesaria, P., Barbara, P., Matteo, M., Maria, F., Do- menico, De C., Annalisa, I., Sante, U., Gianfranco, B., Vittorio, S., Francesco, C., Franco, C., and Andrea, M. (2001) Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)-dependent plaque instability, Circulation 104, 921-927.
10. Belton, O., Duffy, A., Toomey, S., and Fitzgerald, D. (2003) Cyclooxy- genase isoforms and platelet vessel wall interactions in the apoli- poprotein E knockout mouse model of atherosclerosis, Circulation 108, 3017-3023.
11. Gross, S., Tilly, P., Hentsch, D., Vonesch, J., and Fabre, J. E. (2007) Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors, J. Exp. Med. 204, 3113-3120.
12. Cipollone, F., Fazia, M., Iezzi, A., Cuccurullo, C., Cesare, D., Ucchino, S., Spigonardo, F., Marchetti, A., Buttitta, F., Paloscia, L., Mascel- lanti, M., Cuccurullo, F., and Mezzetti, A. (2005) Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human, Arterioscler., Thromb., Vasc. Biol. 25,1925-19331.
13. Fabre, J., Nguyen, M., Athirakul, K., Coggins, K., McNeish, J., Austin, S., Parise, L., FitzGerald, G., Coffman, T., and Koller, B. (2001) Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation, J. Clin. Invest. 107, 603-610.
14. Sugimoto, Y, and Narumiya, S. (2007) Prostaglandin E receptors, J. Biol. Chem. 282,11613-11617.
15. Breyer, R. M., Bagdassarian, C. K., Myers, S. A., and Breyer, M. D. (2001) Prostanoid receptors: subtypes and signaling, Ann. Rev. Pharmacol. Toxicol. 41, 661-690.
16. Takeuchi, K, Ukawa, H, Furukawa, O, Kawauchi, S, Araki, H, Sugi- moto, Y, Ishikawa, A, Ushikubi, F, and Narumiya, S. (1999) Prostaglandin E receptor subtypes involved in stimulation of gastroduode- nal bicarbonate secretion in rats and mice, J. Physiol. Pharmacol. 50, 155-167.
17. Paul, B., Ashby, B., and Sheth, S. (1998) Distribution of prostaglandin IP and EP receptorsubtypes and isoforms in platelets and human umbilical artery smooth muscle cells, Br. J. Haematol. 102, 1204 -1211.
18. Ma, H., Hara, A., Xiao, C. Y., Okada, Y., Takahata, O., Nakaya, K., Sugimoto, Y., Ichikawa, A., Narumiya, S., and Ushikubi, F. (2001) Increased bleeding tendency and decreased susceptibility to throm- boembolism in mice lacking the prostaglandin E receptor subtype EP(3), Circulation 104,1176-1180.
19. Juteau, H., Gareau, Y., Labelle, M., Sturino, C., Sawyer, N., Trem- blay, N., Lamontagne, S., Carriere, M., Denis, D., and Metters, K. (2001) Structure-activity relationship of cinnamic acylsulfonamide analogues on the human EP3 prostanoid receptor, Bioorg. Med. Chem. 9,1977-1984.
20. Selected compounds were incubated with rat liver microsomes and incubates were followed using LC-MS-MS analysis for metabolic profile. For example, analog 4 (Supplementary Table ST-1) showed M+16 and M+32 metabolites, consistent with mono- and bis- oxidation derived metabolites.
21. Tranilast containing an a,B-unsaturated amide functionality has been reported to be launched in Japan and Korea for the treatment of allergic rhinitis, asthma, and atopic dermatitis by Kissei Pharmaceuticals Co., Ltd. Data source http://www.iddb3.com.
22. For a report that substituents that are particularly effective in stabilizing nucleophilic addition to a,B-unsaturated carbonyl compounds include aldehydes, ketone, esters and other carboxylic acid derivatives except amide, see:Carroll, F. (1998) Perspectives on Structure and Mechanism in Organic Chemistry,pp 628-629, Brooks/Cole Publishing Co., Pacific Grove, CA
23. PerlmutterP. (1992) Conjugate Addition Reaction in Organic Synthesis, Pergamon Press, Oxford, England.
24. Palomo, C., Oiarbide, M., Dias, F., Ortiz, A., and Linden, A. (2001) J. Am. Chem. Soc. 123, 5602-5603. This source reports that reaction of N-enolyoxazolidine-2-thionewith Lewis acids yields, after hy- drolytic workup, the corresponding B-metcapto carbonyl adducts. This reaction represents intramolecular addition of thiol to a tertiary amide surrogate.
25. Reaction of methyl cinnamate and O-tert-butyldimethyl silyl cin- namate with N-BOC cystamine in MeOH/NaOMe for 12 h at RT provided 68% and 64% yield of the corresponding Michael adducts, respectively,whereas undersimilarreactions conditions neithercin- namide nor cinnamic acid yielded any desired adduct.
26. Kawasaki, T., Ozeki, Y., Igawa, T., and Kambayashi, J. (2000) Increased platelet sensitivity to collagen in individuals resistant to low-dose aspirin, Stroke 31, 591-595.
27. Heptinstall, S., Iue Espinosa, D., Manolopoulos, P., Glenn, J. R., White, A. E., Johnson, A., Dovlatova, N., Fox, S. C., May, J. A., Hermann, D., Magnusson, O., Stefansson, K., Hartman, D., and Gur- ney, M. (2008)DG-041 inhibits the EP3 prostanoid receptor-a new target for inhibition of platelet function in atherothrombotic disease, Platelets 19, 605- 613.
28. Wise, H., Wong, Y., and Jones, R. (2002) Prostanoid signal integration and cross talk, Neurosignals 11, 20-28.
29. Sugidachi, A., Asai, F., Ogawa, T., Inoue, T., and Koike, H. (2000) The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties, Br. J. Pharmacol. 129,1439-1446.
30. Burt, C., Richards, W. G., and Huxley, P. (1990) The application of molecular similarity calculations, J. Comput. Chem. 11, 1139-1146.
31. Carbo, R., Ledya, L., and Arnau, M. (1980) How similar is a molecule to another? An electron density measure of similarity between two molecular structures, Int. J. Quantum Chem. 17,1185-1189.