Discovery and structure-activity studies of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors

Connolly, Cleo J.; Hamby, James M.; Schroeder, Mel C.; Barvian, Mark R.; Lu, Gina H.; Panek, Robert L.; Amar, Aneesa M.; Shen, Cindy; Kraker, Alan J.; Fry, David W.; Klohs, Wayne D.; Doherty, Annette M.

doi:10.1016/s0960-894x(97)00445-9

Cited by 66 publications

(38 citation statements)

References 13 publications

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“…The obstacles to identifying selective inhibitors are the large number of TKs that have been described and the structural homology between the TKs, especially in their ATP-binding regions. 9 Despite these difficulties several selective TK inhibitors have been identified including those of EGFr [27][28][29][30][31][32][33][34][35] and FGFr TK [36][37][38] activity reported by Parke-Davis. We were also interested in identifying compounds that could selectively modulate the activity of PDGFr TK due to the importance of PDGF and its receptors in cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Boschelli¹,

Wu²,

Klutchko³

et al. 1998

J. Med. Chem.

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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[2,3-d]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.

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Section: Introductionmentioning

confidence: 99%

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

Boschelli¹,

Wu²,

Klutchko³

et al. 1998

J. Med. Chem.

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“…115 Subsequent studies led to the synthesis of potent dual Src/Abl inhibitors: compound 18 (PD 166326) (Fig. 6) showed IC 50 values of 6 and 8 nM for Src and Abl, respectively.…”

Section: Pyrido[23-d]pyrimidinesmentioning

confidence: 99%

New insights into small‐molecule inhibitors of Bcr‐Abl

Schenone

Bruno

Radi

et al. 2010

Medicinal Research Reviews

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Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a defined genetic abnormality, the Bcr-Abl fusion gene on the Philadelphia chromosome that expresses the constitutively activated tyrosine kinase (TK) Bcr-Abl. This enzyme leads to the malignant transformation of primitive hematopoietic cells and to the consequent disease. The central role of Bcr-Abl in the pathogenesis of CML culminated in the discovery of imatinib (an ATP-competitive inhibitor), which is currently the frontline therapy for CML. Unfortunately, the initial enthusiasm generated by its high response rate has been dampened by the development of resistance, especially in the advanced phases of CML. To overcome imatinib resistance, several second-generation ATP-competitive inhibitors endowed with increased potency against imatinib-resistant mutants have been developed: the dual Src/Abl inhibitor dasatinib and the Abl inhibitor nilotinib have been recently approved by US-FDA for the treatment of imatinib-resistant CML, and many other compounds are currently in clinical trial. Although second-generation TK inhibitors have shown to be clinically effective against most of the imatinib-resistant mutants, to date poor results have been obtained in the treatment of the Bcr-Abl T315I mutant. In this review we will report the most interesting second-generation Abl and dual Src/Abl inhibitors recently entered in clinical trial, but also the new ATP-competitive and uncompetitive inhibitors published in the last few years, focusing on their chemical structure, mechanism of action, and structure-activity relationship.

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“…They are effective because the sulfonamide acts synergistically by arresting the production of dihydrofolic acid from p-aminobenzoic acid, thus achieving a double (sequential) blockade of the folate pathway in the microorganism, which (unlike man) cannot use preformed folic acid. Diaminopyrimidine derivatives trimetrexate, piritrexim and several fused pyrimidines and pyrido [2,3- Pyrido[2,3-d]pyrimidine ring system is present in a number of biologically active compounds which includes antitumor [9], antipyretic [10], analgesic [11], antihistaminic [12], PDE4 inhibitor [13], adenosine kinase inhibitor [14], tyrosine kinase inhibitor [15] and diuretic [16,17] activities. More specifically pyrido [2,3-d]pyrimidines were considered as inhibitors of Pneumocystis carinii, Toxoplasma gondii of tumor cells in culture.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of new 2-substituted pyrido[2,3-d]pyrimidin-4(1H)-ones and their antibacterial activity☆

Narayana

Rao

Rao³

2009

European Journal of Medicinal Chemistry

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Discovery and structure-activity studies of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors

Cited by 66 publications

References 13 publications

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

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

New insights into small‐molecule inhibitors of Bcr‐Abl

Synthesis of new 2-substituted pyrido[2,3-d]pyrimidin-4(1H)-ones and their antibacterial activity☆

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