Discovery of 2-(phenoxypyridine)-3-phenylureas as small molecule P2Y 1 antagonists

Journal of Medicinal Chemistry

Volumn 56, Issue 4, 2013, Pages 1704-1714

  Chao, Hannguang ^a   Turdi, Huji ^a   Herpin, Timothy F ^a   Roberge, Jacques Y ^a   Liu, Yalei ^a   Schnur, Dora M ^a   Poss, Michael A ^a   Rehfuss, Robert ^a   Hua, Ji ^a   Wu, Qimin ^a   Price, Laura A ^a   Abell, Lynn M ^a   Schumacher, William A ^a   Bostwick, Jeffrey S ^a   Steinbacher, Thomas E ^a   Stewart, Anne B ^a   Ogletree, Martin L ^a   Huang, Christine S ^a   Chang, Ming ^a   Cacace, Angela M ^a   Arcuri, Maredith J ^a   Celani, Deborah ^a   Wexler, Ruth R ^a   Lawrence, R Michael ^a   more..

^a BRISTOL MYERS SQUIBB RESEARCH AND DEVELOPMENT   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 CHLOROPHENYL) 3 [2 (3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (2 FLUOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (2,4 DIFLUOROPHENYL) 3 (2 PHENOXYPYRIDIN 3 YL)UREA; 1 (2,4 DIFLUOROPHENYL) 3 [2 (2 ISOPROPYLPHENOXY]PYRIDIN 3 YL]UREA; 1 (2,4 DIFLUOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (3 CHLOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL)UREA; 1 (3 FLUOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (3,4 CHLOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (3,5 CHLOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 CHLOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 CYANOPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 DIMETHYLAMINOPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 FLUOROPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 METHOXYPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 METHYLPHENYL) 3 [2 (3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (4 TERT BUTYLPHENYL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 (BIPHENYL 4 YL) 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 BENZYL 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 PHENETHYL 3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREA; 1 [2 (2 TERT BUTYLPHENOXY)PYRIDIN 3 YL) 3 4 (TRIFLUOROMETHOXY]PHENYLUREA; 1 [2 (2 TERT BUTYLPHENOXY)PYRIDIN 3 YL] 3 (2,4 DIFLUOROPHENYL)UREA; 1 [2 (3 TERT BUTYLPHENOXY)PYRIDIN 3 YL] 3 (2,4 DIFLUOROPHENYL)UREA; 1 [4 (TRIFLUOROMETHOXY)PHENYL] 3 [2 [3 (TRIFLUOROMETHYL) PHENOXY]PYRIDIN 3 YL]UREA; 3 AMINO 2 PHENOXYPYRIDINE; 3 NITRO 2 PHENOXYPYRIDINE; ANTICOAGULANT AGENT; CLOPIDOGREL; METHYL 4 [3 [2 [3 (TRIFLUOROMETHYL)PHENOXY]PYRIDIN 3 YL]UREIDO]BENZOATE; PURINERGIC P2Y RECEPTOR ANTAGONIST; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTERY THROMBOSIS; ARTICLE; BINDING AFFINITY; BLEEDING TIME; BLOOD SAMPLING; CONTROLLED STUDY; DRUG IDENTIFICATION; DRUG SAFETY; MALE; NONHUMAN; PROCESS OPTIMIZATION; RAT;

EID: 84874618577     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301708u     Document Type: Article

References (37)

1. 1 Receptor Biochem. Biophys. Res. Commun. 1996, 221, 588-593 (Pubitemid 26153908)
2. Boeynaems, J. M.; Bernard, R.; Rodolphe, J.; Nathalie, S.-H.; Didier, C. Overview of P2Y Receptors as Therapeutic Targets Drug Dev. Res. 2001, 52, 187-189
3. Abbracchio, M. P.; Burnstock, G.; Boeynaems, J. M.; Barnard, E. A.; Boyer, J. L.; Kennedy, C.; Knight, G. E.; Fumagalli, M.; Gachet, C.; Jacobson, K. A.; Weisman, G. A. International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: from Molecular Mechanisms and Pathophysiology to Therapy Pharmacol. Rev. 2006, 58, 281-341 (Pubitemid 44394905)
4. Burnstock, G.; Williams, M. P2 Purinergic Receptors: Modulation of Cell Function and Therapeutic Potential J. Pharm. Exp. Ther. 2000, 295, 862-869
5. Jacobson, K. A; Boeynaems, J.-M. P2Y Nucleotide Receptors: Promise of Therapeutic Applications Drug Discovery Today 2010, 15, 570-578
6. 2+ Signals in Cultured Aortic Smooth Muscle Cells Purinergic Signalling 2012, 8, 763-777
7. Jacobson, K. A.; Jayasekara, M. P.; Costanzi, S. Molecular Structure of P2Y Receptors: Mutagenesis, Modeling, and Chemical Probes WIREs Membr. Transp. Signaling 2012, 1, 815-827
8. Abbracchio, M. P.; Burnstock, G. Purinoceptors: Are There Families of P2X and P2Y Purinoceptors? Pharmacol. Ther. 1994, 64, 445-475 (Pubitemid 24381231)
9. 6 Receptors on Cardiomyocytes and Release of UTP in Man During Myocardial Infarction Circ. Res. 2006, 98, 970-976
10. Raju, N. C.; Eikelboom, J. W.; Hirsh, J. Platelet ADP-Receptor Antagonists for Cardiovascular Disease: Past, Present and Future Nat. Clin. Pract. Cardiovasc. Med. 2008, 5, 766-780
11. Hollopeter, G.; Jantzen, H. M.; Vincent, D.; Li, G.; England, L.; Ramakrishnan, V.; Yang, R.-B.; Nurden, P.; Nurden, A.; Julius, D.; Conley, P. B. Identification of the Platelet ADP Receptor Targeted by Antithrombotic Drugs Nature 2001, 409, 202-207 (Pubitemid 32144286)
12. Pereillo, J. M.; Maftouh, M.; Andrieu, A.; Uzabiaga, M. F.; Fedeli, O.; Savi, P.; Pascal, M.; Herbert, J. M.; Maffrand, J. P.; Picard, C. Structure and Stereochemistry of the Active Metabolite of Clopidogrel Drug Metab. Dispos. 2002, 30, 1288-1295 (Pubitemid 35265838)
13. 12 Antagonist AZD6140 with Aspirin in Patients with Atherosclerosis: a Double-Blind Comparison to Clopidogrel with Aspirin Eur. Heart J. 2006, 27, 1038-1047
14. Jernberg, T.; Payne, C. D.; Winters, K. J.; Darstein, C.; Brandt, J. T.; Jakubowski, J. A.; Naganuma, H.; Siegbahn, A.; Wallentin, L. Prasugrel Achieves Greater Inhibition of Platelet Aggregation and a Lower Rate of Non-Responders Compared with Clopidogrel in Aspirin-Treated Patients with Stable Coronary Artery Disease Eur. Heart J. 2006, 27, 1166-117
15. Jakubowski, J. A.; Winters, K. J.; Naganuma, H.; Wallentin, L. Prasugrel: a Novel Thienopyridine Antiplatelet Agent. A Review of Preclinical and Clinical Studies and the Mechanistic Basis for its Distinct Antiplatelet Profile Cardiovasc. Drug Rev. 2007, 25, 357-374 (Pubitemid 350233359)
16. Ingall, A. H.; Dixon, J.; Bailey, A.; Coombs, M. E.; Cox, D.; McInally, J. I.; Hunt, S. F.; Kindon, N. D.; Teobald, B. J.; Willis, P. A.; Humphries, R. G.; Leff, P.; Clegg, J. A.; Smith, J. A.; Tomlinson, W. Antagonists of the Platelet P2T Receptor: a Novel Approach to Antithrombotic Therapy J. Med. Chem. 1999, 42, 213-220 (Pubitemid 29069856)
17. Humphries, R. G.; Tomlinson, W.; Ingall, A. H.; Cage, P. A.; Leff, P. FPL 66096: a Novel, Highly Potent and Selective Antagonist at Human Platelet P2T-Purinoceptors Br. J. Pharmacol. 1994, 113, 1057-1063 (Pubitemid 24326854)
18. Y12 Receptor Antagonist for the Prevention of Thrombosis Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018 (Pubitemid 47446193)
19. Y12 Inhibitors Circulation 2010, 121, 171-179
20. 1 Antagonist Circulation 2001, 103, 718-723 (Pubitemid 32144201)
21. 1 Receptors by N6-Methyl 2′-Deoxyadenosine 3′,5′-Bisphosphate Br. J. Pharmacol. 1998, 124, 1-3 (Pubitemid 28210035)
22. Tantry, U. S.; Bliden, K. P.; Gurbel, P. A. AZD6140 Expert Opin. Invest. Drugs 2007, 16, 225-229 (Pubitemid 46206636)
23. 1 Receptors J. Med. Chem. 1998, 41, 183-190 (Pubitemid 28114360)
24. Kim, H. S.; Ohno, M.; Xu, B.; Kim, H. O.; Choi, Y.; Ji, X. D.; Maddileti, S.; Marquez, V. E.; Harden, T. K.; Jacobson, K. A. Modeling the Adenosine Receptors: Comparison of the Binding Domains of A2A Agonists and Antagonists J. Med. Chem. 2003, 46, 4847-4859 (Pubitemid 37352025)
25. 1 Receptor Ligands J. Med. Chem. 2000, 43, 829-842 (Pubitemid 30152292)
26. 1 Receptor: Structure-Activity Relationships and Receptor Docking J. Med. Chem. 2001, 44, 3092-3108 (Pubitemid 32862340)
27. 1 Receptor Agonists J. Med. Chem. 2002, 45, 5384-5396 (Pubitemid 35429177)
28. 2 Receptors J. Med. Chem. 2006, 49, 1980-1990
29. 1 Receptors for the Treatment of Thromboembolic Disorders. WO2005/1133511 A1, 2005.
30. 1 Receptor Antagonists as Novel Antithrombotic Agents Bioorg. Med. Chem. Lett. 2008, 18, 3338-3343 (Pubitemid 351721005)
31. Morales-Ramos, A. I.; Mecom, J. S.; Kiesow, T. J.; Graybill, T. L.; Brown, G. D.; Aiyar, N. V.; Davenport, E. A.; Kallal, L. A.; Knapp-Reed, B. A.; Li, P.; Londregan, A. T.; Morrow, D. M.; Senadhi, S.; Thalji, R. K.; Zhao, S.; Burns-Kurtis, C. L.; Marino, J. P., Jr. Tetrahydro-4-quinolinamines Identified as Novel P2Y(1) Receptor Antagonists Bioorg. Med. Chem. Lett. 2008, 18, 6222-6226
32. 1 Receptor Antagonists Bioorg. Med. Chem. Lett. 2010, 20, 4104-4107
33. 1 Receptor Antagonists Bioorg. Med. Chem. Lett. 2010, 20, 5254-5261
34. Schumacher, W. A.; Bostwick, J. S.; Ogletree, M. L.; Stewart, A.; Steinbacher, T. E.; Hua, J.; Price, L.; Wong, P. C.; Rhefuss, R. Biomarker Optimization to Track the Antithrombotic and Hemostatic Effects of Clopidogrel in Rats J. Pharmacol. Exp. Ther. 2007, 322, 369-377 (Pubitemid 46956346)
35. Sigurdsson, S.; Seeger, B.; Kutzke, U.; Eckstein, F. A Mild and Simple Method for the Preparation of Isocyanates from Aliphatic Amines Using Trichloromethyl Chloroformate. Synthesis of an Isocyanate Containing an Activated Disulfide J. Org. Chem. 1996, 61, 3383-3384
36. Platelet aggregation assays were performed in PRP as described in Platelet Protocols: Research and Clinical Laboratory Procedures; White, M. M.; Jennings, L. K., Eds.; Academic Press: New York, 1999, using 30 μM agatroban (GSK) as the anticoagulant and 2.5 μM ADP as the agonist. Aggregation data were analyzed as area under the curve (AUC) for 5 min.
37. 12 Binding Characteristics and Antithrombotic and Bleeding Effects in Rat and Dog Models of Thrombosis/Hemostasis Thromb. Res. 2009, 124, 565-571