Structure-activity relationships for a novel series of pyrido[2,3- d]pyrimidine tyrosine kinase inhibitors

Journal of Medicinal Chemistry

Volumn 40, Issue 15, 1997, Pages 2296-2303

  Hamby, James M ^a,b   Connolly, Cleo J C ^a,b   Schroeder, Mel C ^a,b   Winters, R Thomas ^a,b   Showalter, H D Hollis ^a,b   Panek, Robert L ^a,c   Major, Terry C ^a,c   Olsewski, Bronislawa ^a,c   Ryan, Michael J ^a,c   Dahring, Tawny ^a,c   Lu, Gina H ^a,c   Keiser, Joan ^a,c   Amar, Aneesa ^a,c   Shen, Cindy ^a,c   Kraker, Alan J ^a,c   Slintak, Veronika ^a,c   Nelson, James M ^a,c   Fry, David W ^a,c   Bradford, Laura ^a,c   Hallak, Hussein ^a,c   Doherty, Annette M ^a,b   more..

^a PFIZER INC   (United States)

^b Depts Cardiovasc Cancer P   (United States)

^c Dept of Vasc and Cardiac Diseases ^*

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 AMINO 6 (3,5 DIMETHOXYPHENYL)PYRIDO[2,3 D]PYRIMIDIN 7 YL] 3 TERT BUTYLUREA; 1 TERT BUTYL 3 [6 (2,6 DICHLOROPHENYL) 2 [[4 (DIETHYLAMINO)BUTYL]AMINO]PYRIDO[2,3 D]PYRIMIDIN 7 YL]UREA; 2 AMINO 7 (3 TERT BUTYLUREIDO) 6 (2,6 DICHLOROPHENYL)PYRIDO[2,3 D]PYRIMIDINE; EPIDERMAL GROWTH FACTOR RECEPTOR; FIBROBLAST GROWTH FACTOR RECEPTOR; PD 161570; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; PYRIDO[2,3 D]PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CARDIOVASCULAR DISEASE; CELL PROLIFERATION; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG SOLUBILITY; DRUG SYNTHESIS; INTRAPERITONEAL DRUG ADMINISTRATION; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; STRUCTURE ACTIVITY RELATION; VASCULAR SMOOTH MUSCLE;

ANIMALS; CELL DIVISION; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; ENZYME INHIBITORS; MAGNETIC RESONANCE SPECTROSCOPY; MUSCLE, SMOOTH, VASCULAR; PYRIMIDINES; RATS; RECEPTOR PROTEIN-TYROSINE KINASES; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 14444281388     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970367n     Document Type: Article

References (55)

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40. For recent examples of ATP competitive tyrosine kinase inhibitors, see: (a) Faltynek, Connie R.; Wang, Su; Miller, Deborah; Mauvais, Patricia; Gauvin, Bruce; Reid, John; Xie, Wen; Hoekstra, Susan; Juniewicz, Paul; et al. Inhibition of T lymphocyte activation by a novel p561ck tyrosine kinase inhibitor. J. Enzyme Inhib. 1995, 9, 111-122. (b) Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter, H. D.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine kinase inhibitors: unusually steep structure-activity relationship for analogs of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J. Med. Chem. 1996, 39, 267-276. (c) Connolly, C. J. C.; Hamby, J. M.; Schroeder, M. C.; Lu, G. H.; Panek, R. L.; Amar, A.; Shen, C.; Kraker, A. J.; Doherty, A. M. Structure-activity relationships of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase. 211th ACS National Meeting, New Orleans, LA, March 24-28 (1996), MEDI-193. (d) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1221-1226. (e) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N. 4-(Phenyl-amino)pyrrolopyrimidines: Potent and Selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem. 1996, 39, 2285-2292.
41. For recent examples of ATP competitive tyrosine kinase inhibitors, see: (a) Faltynek, Connie R.; Wang, Su; Miller, Deborah; Mauvais, Patricia; Gauvin, Bruce; Reid, John; Xie, Wen; Hoekstra, Susan; Juniewicz, Paul; et al. Inhibition of T lymphocyte activation by a novel p561ck tyrosine kinase inhibitor. J. Enzyme Inhib. 1995, 9, 111-122. (b) Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter, H. D.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine kinase inhibitors: unusually steep structure-activity relationship for analogs of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J. Med. Chem. 1996, 39, 267-276. (c) Connolly, C. J. C.; Hamby, J. M.; Schroeder, M. C.; Lu, G. H.; Panek, R. L.; Amar, A.; Shen, C.; Kraker, A. J.; Doherty, A. M. Structure-activity relationships of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase. 211th ACS National Meeting, New Orleans, LA, March 24-28 (1996), MEDI-193. (d) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1221-1226. (e) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N. 4-(Phenyl-amino)pyrrolopyrimidines: Potent and Selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem. 1996, 39, 2285-2292.
42. For recent examples of ATP competitive tyrosine kinase inhibitors, see: (a) Faltynek, Connie R.; Wang, Su; Miller, Deborah; Mauvais, Patricia; Gauvin, Bruce; Reid, John; Xie, Wen; Hoekstra, Susan; Juniewicz, Paul; et al. Inhibition of T lymphocyte activation by a novel p561ck tyrosine kinase inhibitor. J. Enzyme Inhib. 1995, 9, 111-122. (b) Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter, H. D.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine kinase inhibitors: unusually steep structure-activity relationship for analogs of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J. Med. Chem. 1996, 39, 267-276. (c) Connolly, C. J. C.; Hamby, J. M.; Schroeder, M. C.; Lu, G. H.; Panek, R. L.; Amar, A.; Shen, C.; Kraker, A. J.; Doherty, A. M. Structure-activity relationships of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase. 211th ACS National Meeting, New Orleans, LA, March 24-28 (1996), MEDI-193. (d) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1221-1226. (e) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N. 4-(Phenyl-amino)pyrrolopyrimidines: Potent and Selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem. 1996, 39, 2285-2292.
43. For recent examples of ATP competitive tyrosine kinase inhibitors, see: (a) Faltynek, Connie R.; Wang, Su; Miller, Deborah; Mauvais, Patricia; Gauvin, Bruce; Reid, John; Xie, Wen; Hoekstra, Susan; Juniewicz, Paul; et al. Inhibition of T lymphocyte activation by a novel p561ck tyrosine kinase inhibitor. J. Enzyme Inhib. 1995, 9, 111-122. (b) Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter, H. D.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine kinase inhibitors: unusually steep structure-activity relationship for analogs of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J. Med. Chem. 1996, 39, 267-276. (c) Connolly, C. J. C.; Hamby, J. M.; Schroeder, M. C.; Lu, G. H.; Panek, R. L.; Amar, A.; Shen, C.; Kraker, A. J.; Doherty, A. M. Structure-activity relationships of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase. 211th ACS National Meeting, New Orleans, LA, March 24-28 (1996), MEDI-193. (d) Zimmermann, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and highly selective PDGF-receptor autophosphorylation inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1221-1226. (e) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N. 4-(Phenyl-amino)pyrrolopyrimidines: Potent and Selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. J. Med. Chem. 1996, 39, 2285-2292.
44. Dahring, T. K.; Lu, G. H.; Hamby, J. M.; Batley, B. L.; Kraker, A. J.; Panek R. L. Inhibition of growth factor mediated tyrosine phosphorylation in vascular smooth muscle cells by PD 089828, A new synthetic protein tyrosine kinase inhibitor. J. Pharmacol. Exp. Ther. 1997, 282, 1-11.
45. For EGF tyrosine kinase inhibition assay conditions, see: (a) Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L. A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.; Bridges, A. J. A specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase. Science 1994, 265, 1093-1095. (b) Thompson, A. M.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine kinase inhibitors. 2. Synthesis of 2,2′-dithiobis(1H-indole-3-alkanmides) and investigation of their inhibitory activity against epidermal growth factor receptor and pp60v-src protein tyrosine kinases. J. Med. Chem. 1994, 37, 598-608.
46. For EGF tyrosine kinase inhibition assay conditions, see: (a) Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L. A.; Nelson, J. M.; Leopold, W. R.; Connors, R. W.; Bridges, A. J. A specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase. Science 1994, 265, 1093-1095. (b) Thompson, A. M.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine kinase inhibitors. 2. Synthesis of 2,2′-dithiobis(1H-indole-3-alkanmides) and investigation of their inhibitory activity against epidermal growth factor receptor and pp60v-src protein tyrosine kinases. J. Med. Chem. 1994, 37, 598-608.
47. For c-src tyrosine kinase inhibition assay conditions, see: (a) Reference 19b. (b) Rewcastle, G. W.; Palmer, B. D.; Dobrusin, E. M.; Fry, D. W.; Kraker, A. J.; Denny, W. A. Tyrosine Kinase Inhibitors. 3. Structure-activity relationships for inhibition of protein tyrosine kinases by nuclear-substituted derivatives of 2,2′-dithiobis(1-methyl-N-phenyl-1H-indole-3-carboxamide). J. Med. Chem. 1994, 37, 2033-2042.
48. For insulin receptor (InsR) tyrosine kinase inhibition assay conditions, see: Fry, D. W.; Kraker, A. J.; Connors, R. C.; Elliott, W. L.; Nelson, J. M.; Showalter, H. D. H.; Leopold, W. R. Strategies for the discovery of novel tyrosine kinase inhibitors with anticancer activity. Anticancer Drug Des. 1994, 9, 331-351.
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