- Chemically Diverse Group i p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window
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p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.
- Rudolph, Joachim,Murray, Lesley J.,Ndubaku, Chudi O.,O'Brien, Thomas,Blackwood, Elizabeth,Wang, Weiru,Aliagas, Ignacio,Gazzard, Lewis,Crawford, James J.,Drobnick, Joy,Lee, Wendy,Zhao, Xianrui,Hoeflich, Klaus P.,Favor, David A.,Dong, Ping,Zhang, Haiming,Heise, Christopher E.,Oh, Angela,Ong, Christy C.,La, Hank,Chakravarty, Paroma,Chan, Connie,Jakubiak, Diana,Epler, Jennifer,Ramaswamy, Sreemathy,Vega, Roxanne,Cain, Gary,Diaz, Dolores,Zhong, Yu
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p. 5520 - 5541
(2016/07/06)
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- PYRIMIDINE COMPOUNDS AS KINASE INHIBITORS
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This disclosure relates to compounds, methods for their preparation, pharmaceutical compositions including these compounds and methods for the treatment of cellular proliferative disorders, including, but not limited to, cancer.
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Page/Page column 61;62
(2014/10/04)
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- Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5)
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The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure-activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6- carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30-100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure-activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
- Reddy, M. V. Ramana,Akula, Balireddy,Cosenza, Stephen C.,Athuluridivakar, Saikrishna,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Billa, Vinay K.,Subbaiah, D. R. C. Venkata,Bharathi, E. Vijaya,Vasquez-Del Carpio, Rodrigo,Padgaonkar, Amol,Baker, Stacey J.,Reddy, E. Premkumar
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p. 578 - 599
(2014/03/21)
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- Discovery of 6-(2,4-difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl) propylamino]-8-methyl-8 H -pyrido[2,3- d ]pyrimidin-7-one (pamapimod) and 6-(2,4-difluorophenoxy)-8-methyl-2-(tetrahydro-2 H -pyran-4-ylamino)pyrido[2,3- d ]pyrimidin-7(8 H)-one (R1487) as orally bioavailable and highly selective inhibitors of p38α mitogen-activated protein kinase
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The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.
- Goldstein, David M.,Soth, Michael,Gabriel, Tobias,Dewdney, Nolan,Kuglstatter, Andreas,Arzeno, Humberto,Chen, Jeffrey,Bingenheimer, William,Dalrymple, Stacie A.,Dunn, James,Farrell, Robert,Frauchiger, Sandra,La Fargue, Joann,Ghate, Manjiri,Graves, Bradford,Hill, Ronald J.,Li, Fujun,Litman, Renee,Loe, Brad,McIntosh, Joel,McWeeney, Daniel,Papp, Eva,Park, Jaehyeon,Reese, Harlan F.,Roberts, Richard T.,Rotstein, David,San Pablo, Bong,Sarma, Keshab,Stahl, Martin,Sung, Man-Ling,Suttman, Rebecca T.,Sjogren, Eric B.,Tan, Yunchou,Trejo, Alejandra,Welch, Mary,Weller, Paul,Wong, Brian R.,Zecic, Hasim
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p. 2255 - 2265
(2011/06/21)
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- KINASE INHIBITORS USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.
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Page/Page column 90
(2008/06/13)
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- A facile, KF/Al2O3 mediated method for the preparation of functionalized pyrido[2,3-d]pyrimidin-7(8H)-ones
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A series of functionalized pyrido[2,3-d]pyrimidin-7(8H)-ones were prepared by a KF/Al2O3 mediated condensation of 4-(alkylamino)-2-(methylthio)pyrimidine-5-carbaldehydes and phenyl acetic acid ester derivatives.
- Blass, Benjamin E.,Coburn, Keith,Fairweather, Neil,Sabat, Mark,West, Laura
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p. 3177 - 3180
(2007/10/03)
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- Pyridopyrimidinone derivatives for treatment of neurodegenerative disease
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This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferatives disorders, such as cancer and restenosis. We have now discovered a group of 7,8-dihydro-2 (amino and thio)pyrido[2,3-d]pyrimidines and 2,4-di
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- 6-ALKOXY-PYRIDO-PYRIMIDINES AS P-38 MAP KINASE INHIBITORS
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The present invention provides compounds of Formula (I), wherein R1 is alkyl, cycloalkyl, cycloakylalkyl, or -CH2-alkenyl, X1 is O, NH, N(alkyl), S or -C(=O), Z is N or CH; and R2 and R3 are as define
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- 2-(4-Pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimdin-7-ones
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This invention provides antiangiogenic compounds of the Formula (I), which are useful for treating diseases, resulting from uncontrolled cellular proliferation such as cancer, atherosclerosis, rheumatoid arthritis, and psoriasis. 1
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- 6-Substituted pyrido-pyrimidines
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The present invention provides compounds of the Formula I and II: wherein R1, R3, W, Z, X1, X2, Ar1, R8 and R9 are as defined herein, and methods and intermediates for their preparation and uses thereof.
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- Pyrido[2,3-D]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation
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This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferative disorders, such as cancer and restenosis. We have now discovered a group of 7,8-dihydro-2-(amino and thio)pyrido[2,3-d]pyrimidines and 2,4-dia
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- Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases
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The identification of 8-ethyl-2-phenylamino-8H-pyrido [2,3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido [2,3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of m
- Barvian,Boschelli,Cossrow,Dobrusin,Fattaey,Fritsch,Fry,Harvey,Keller,Garrett,La,Leopold,McNamara,Quin,Trumpp-Kallmeyer,Toogood,Wu,Zhang
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p. 4606 - 4616
(2007/10/03)
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- 2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones. Structure-activity relationships against selected tyrosine kinases and in vitro and in vivo anticancer activity
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While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2,3- d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was devel
- Klutchko, Sylvester R.,Hamby, James M.,Boschelli, Diane H.,Wu, Zhipei,Kraker, Alan J.,Amar, Aneesa M.,Hartl, Brian G.,Shen, Cynthia,Klohs, Wayne D.,Steinkampf, Randall W.,Driscoll, Denise L.,Nelson, James M.,Elliott, William L.,Roberts, Billy J.,Stoner, Chad L.,Vincent, Patrick W.,Dykes, Donald J.,Panek, Robert L.,Lu, Gina H.,Major, Terry C.,Dahring, Tawny K.,Hallak, Hussein,Bradford, Laura A.,Showalter, H. D. Hollis,Doherty, Annette M.
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p. 3276 - 3292
(2007/10/03)
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