1. Academic Validation
  2. 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

  • J Med Chem. 1998 Oct 22;41(22):4365-77. doi: 10.1021/jm980398y.
D H Boschelli 1 Z Wu S R Klutchko H D Showalter J M Hamby G H Lu T C Major T K Dahring B Batley R L Panek J Keiser B G Hartl A J Kraker W D Klohs B J Roberts S Patmore W L Elliott R Steinkampf L A Bradford H Hallak A M Doherty
Affiliations

Affiliation

  • 1 Departments of Medicinal Chemistry, Cancer Research, Vascular, Cardiac Diseases, Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. bosched@war.wyeth.com
Abstract

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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