Potent N-(1,3-Thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel

Journal of Medicinal Chemistry

Volumn 47, Issue 25, 2004, Pages 6363-6372

  Bilodeau, Mark T ^a   Balitza, Adrienne E ^a   Koester, Timothy J ^a   Manley, Peter J ^a   Rodman, Leonard D ^a   Buser Doepner, Carolyn ^a   Coll, Kathleen E ^a   Fernandes, Christine ^a   Gibbs, Jackson B ^a   Heimbrook, David C ^a   Huckle, William R ^a   Kohl, Nancy ^a   Lynch, Joseph J ^a   Mao, Xianzhi ^a   McFall, Rosemary C ^a   McLoughlin, Debra ^a   Miller Stein, Cynthia M ^a   Rickert, Keith W ^a   Sepp Lorenzino, Laura ^a   Shipman, Jennifer M ^a   Subramanian, Raju ^a   Thomas, Kenneth A ^a   Wong, Bradley K ^a   Yu, Sean ^a   Hartman, George D ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4 MORPHOLIN 4 YLMETHYLPYRIDIN 2 YLAMINO)THIAZOLE 5 CARBONITRILE; 2 (4 PIPERAZIN 1 YLMETHYLPYRIDIN 2 YLAMINO)THIAZOLE 5 CARBONITRILE; 2 [4 (4 ACETYLPIPERAZIN 1 YLMETHYL)PYRIDIN 2 YLAMINO]THIAZOLE 5 CARBONITRILE; 2 [4 [4 (2 HYDROXYETHANOYL)PIPERAZIN 1 YLMETHYL]PYRIDIN 2 YLAMINO]THIAZOLE 5 CARBONITRILE; 2 [[4 [[4 (METHYLSULFONYL)PIPERIDIN 1 YL]METHYL]PYRIDIN 2 YL]AMINO] 1,3 THIAZOLE 5 CARBONITRILE; 4 [2 (5 CYANOTHIAZOL 2 YLAMINO) 3 METHYLPYRIDIN 4 YLMETHYL]PIPERAZINE 1 CARBOXYLIC ACID METHYLAMIDE; 4 [2 (5 CYANOTHIAZOL 2 YLAMINO)PYRIDIN 4 YLMETHYL]PIPERAZINE 1 CARBOXYLIC ACID METHYLAMIDE; 4 [[2 [(5 CYANO 1,3 THIAZOL 2 YL)AMINO] 4 PYRIDINYL]METHYL] 1 PIPERAZINECARBOXAMIDE; 4 [[2 [(5 CYANO 1,3 THIAZOL 2 YL)AMINO] 4 PYRIDINYL]METHYL]N,N DIMETHYL 1 PIPERAZINECARBOXAMIDE; N (1,3 THIAZOL 2 YL)PYRIDIN 2 AMINE; PIPERAZINE DERIVATIVE; POTASSIUM CHANNEL HERG; PROTEIN TYROSINE KINASE INHIBITOR; PYRIDINE DERIVATIVE; THIAZOLE DERIVATIVE; UNCLASSIFIED DRUG; VASCULOTROPIN RECEPTOR;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING AFFINITY; BINDING ASSAY; CHANNEL GATING; CHEMICAL REACTION; CONFORMATIONAL TRANSITION; DOG; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CONFORMATION; DRUG DISPOSITION; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG SOLUBILITY; DRUG SYNTHESIS; DRUG TARGETING; ENDOTHELIUM CELL; ENZYME ASSAY; ENZYME INHIBITION; ENZYME SPECIFICITY; HUMAN; HUMAN CELL; IC 50; IN VIVO STUDY; MALE; MITOGENESIS; NONHUMAN; PHARMACODYNAMICS; PHARMACOKINETICS; POTASSIUM CURRENT; PROTEIN PHOSPHORYLATION; QT PROLONGATION; RAT; RHESUS MONKEY; STRUCTURE ANALYSIS; SUBSTITUTION REACTION; TECHNIQUE; TORSADE DES POINTES;

ADMINISTRATION, ORAL; AMINOPYRIDINES; ANIMALS; BIOLOGICAL AVAILABILITY; CELL LINE; DOGS; ELECTROCARDIOGRAPHY; LUNG; MACACA MULATTA; MALE; MICE; MICROSOMES, LIVER; PHOSPHORYLATION; POTASSIUM CHANNELS, VOLTAGE-GATED; PYRIDINES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; THIAZOLES; TISSUE DISTRIBUTION; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2;

EID: 9744260986     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049697f     Document Type: Article

References (24)

1. (a) Thomas, K. A. Vascular endothelial growth factor, a potent and selective angiogenic agent. J. Biol. Chem. 1996, 271, 603-606.
2. (b) Ferrara, N.; Davis-Smyth, T. The biology of vascular endothelial growth factor. Endocrine Rev. 1997, 18, 4-25.
3. Fox, S. B.; Gasparini, G.; Harris, A. L. Angiogenesis: pathological, prognostic, and growth factor pathways and their link to trial design and anticancer drugs. Lancet Oncol. 2001, 2, 278-289.
4. Neufeld, G.; Cohen, T.; Gengrinovitch, S.; Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB 1999, 13, 9-22.
5. (a) Yang, J. C.; Haworth, L.; Sherry, R. M.; Hwu, P.; Schwartzentruber, D. J.; Topalian, S. L.; Steinberg, S. M.; Chen, H. X.; Rosenberg, S. A. A randomized trial of bevacizumab, an antivascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 2003, 349, 427-34.
6. (b) McCarty M. Antiangiogenesis drug promising for metastatic colorectal cancer: New treatments for colorectal cancer might improve patients' survival, investigators reported at ASCO. Lancet 2003, 361, 1959.
7. For recent reviews, see: (a) Bilodeau, M. T.; Fraley, M. E.; Hartman, G. D. Kinaseinsetdomain-containing receptor kinase inhibitors as antiangiogenic agents. Expert Opin. Investig. Drugs 2002, 11, 737-745.
8. (b) Sepp-Lorenzino, L.; Thomas, K. A. Antiangiogenic agents targeting vascular endothelial growth factor and its receptors in clinical development. Expert Opin. Investig. Drugs 2002, 11, 1447-1465.
9. Bilodeau, M. T.; Rodman, L. D.; McGaughey, G. B.; Coll, K. E.; Koester, T. J.; Hoffman, W. F.; Hungate, R. W.; Kendall, R. L.; McFall, R. C.; Rickert, K. W.; Rutledge, R. Z.; Thomas, K. A. The Discovery of N-(1,3-Thiazol-2-yl) pyridin-2-amines as Potent Inhibitors of KDR Kinase. Bioorg. Med. Chem. Lett. 2004, 14, 2941-2945.
10. Rickert, K.; Coll, K. E.; Mao, X.; McFall, R. C.; Pan, B.-S.; Zeng, Q.; Johnson, A.; Sepp-Lorenzino, L.; Shipman, J. M.; McGaughey, G. B.; Kendall, R. L.; Huckle, W. R.; Brunner, J. E.; Anderson, K. D.; Fraley, M. E.; Hoffman, W. F.; Bilodeau, M. T.; Hartman, G. D.; Heimbrook, D. C.; Gibbs, J. B.; Kohl, N.; Thomas, K. A. Activities of a potent inhibitor of the unactivated form of the human vascular endothelial growth factor receptor KDR. J. Biol. Chem., submitted.
11. Roden, D. M. Drug-induced prolongation of the QT interval. N. Engl. J. Med. 2004, 350, 1013-1022.
12. Cavero, I.; Mestre, M.; Guillon, J.-M.; Crumb, W. Drugs that prolong QT interval as an unwanted side effect: assessing their likelihood of inducing hazardous cardiac dysrhythmias. Exp. Opin. Pharmacother. 2000, 1, 947-973.
13. De Ponti, F.; Poluzzi, E.; Montanaor, N. Organising evidence on QT prolongation and occurrence of Torsades de Pointes with nonantiarrythmic drugs: a call for consensus. Eur. J. Clin. Pharmacol. 2001, 57, 185-209.
14. 6-(hetarylmethyl)guanines having basic rings in the side chain J. Med. Chem. 1998, 41, 5265-5271.
15. Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. An ammonia equivalent for the palladium-catalyzed amination of aryl halides and triflates. Tetrahedron Lett. 1997, 38, 6367-6370.
16. Coperet, C.; Adolfsson, H.; Khuong, T.-A. V.; Yudin, A. K.; Sharpless, K. B. A simple and efficient method for the preparation of pyridine N-oxides. J. Org. Chem. 1998, 63, 1740-1741.
17. Netzer, R.; Ebneth, A.; Bischoff, U.; pongs, O. Screening lead compounds for QT interval prolongation. Drug Discovery Today 2001, 6, 78-84.
18. Skobe, M., Hawighorst, T., Jackson, D. G., Prevo, R., Janes, L., Velasco, P., Riccardi, L., Alitalo, K., Claffey, K., and Detmar, M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 2001, 7, 192-198.
19. Hafez, E. A. A.; Abed, N. M.; Elsakka, I. A. Reactions with heterocyclic diazonium salts. Synthesis of several new azolylhydrazones. J. Heterocycl. Chem. 1983, 20, 285-288.
20. Borthwick, A. D.; Foxton, M. W.; Gray, B. V.; Gregory, G. I.; Seale, P. W.; Warburton, W. K. Some 2-nitrothiazole. J. Chem. Soc., Perkin Trans. 1 1973, 2769-2772.
21. Clarke, K.; Goulding, J.; Scrowston, R. M. Preparation of some thiopyranopyridine derivatives. J. Chem. Soc., Perkin Trans. 1 1984, 1501-1505.
22. 3H]-Dofetilide Binding: Biological Models that Manifest Solely the High or the Low Affinity Binding Site. J. Mol. Cell. Cardiol. 1996, 28, 1085-1096.
23. Zhou, Z.; Gong, Q.; Ye, B.; Fan, Z.; Makielski, J. C.; Robertson, G. A.; January, C. T. Properties of HERG Channels Stably Expressed in HEK 293 Cells Studied at Physiological Temperature. Biophys. J. 1998, 74, 230-241.
24. Kr Potassium Channel Blockers as Class III Antiarrhythmic Agents. In Perspectives in Medicinal Chemistry; Testa, B., Kyburz, E., Fuhrer, W., Giger, R., Eds.; Verlag Helvetica Chimica Acta: Basel, 1993; pp 389-404.