- 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 52; 53; 54
(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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- 5 OXO-5,8-DIHYDROPYRIDO[2,3-d]PYRIMIDINE DERIVATIVES AS CAMKII KINASE INHIBITORS FOR TREATING CARDIOVASCULAR DISEASES
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The present invention relates to 5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine derivatives, to their preparation and to their therapeutic use.
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Page/Page column 15
(2012/11/08)
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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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supporting information; experimental part
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 89
(2008/06/13)
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- Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors
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5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration.
- Ishida, Hiroshi,Isami, Shoichi,Matsumura, Tsutomu,Umehara, Hiroshi,Yamashita, Yoshinori,Kajita, Jiro,Fuse, Eiichi,Kiyoi, Hitoshi,Naoe, Tomoki,Akinaga, Shiro,Shiotsu, Yukimasa,Arai, Hitoshi
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supporting information; experimental part
p. 5472 - 5477
(2009/05/30)
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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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- Synthesis and tyrosine kinase inhibitory activity of a series of 2- amino-8H-pyrido[2,3-d]pyrimidines: Identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors
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Screening of a compound library led to the identification of 2-amino-6- (2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF- dependent cellular assays and blocked the in vivo growth of three PDGF- dependent tumor lines.
- Boschelli, Diane H.,Wu, Zhipei,Klutchko, Sylvester R.,Showalter, H. D. Hollis,Hamby, James M.,Lu, Gina H.,Major, Terry C.,Dahring, Tawny K.,Batley, Brian,Panek, Robert L.,Keiser, Joan,Hartl, Brian G.,Kraker, Alan J.,Klohs, Wayne D.,Roberts, Bill J.,Patmore, Sandra,Elliott, William L.,Steinkampf, Randy,Bradford, Laura A.,Hallak, Hussein,Doherty, Annette M.
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p. 4365 - 4377
(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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