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.
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.
Boschelli
D H
DH
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
Wu
Z
Z
Klutchko
S R
SR
Showalter
H D
HD
Hamby
J M
JM
Lu
G H
GH
Major
T C
TC
Dahring
T K
TK
Batley
B
B
Panek
R L
RL
Keiser
J
J
Hartl
B G
BG
Kraker
A J
AJ
Klohs
W D
WD
Roberts
B J
BJ
Patmore
S
S
Elliott
W L
WL
Steinkampf
R
R
Bradford
L A
LA
Hallak
H
H
Doherty
A M
AM
D016475:3T3 Cells; D000818:Animals; D001682:Biological Availability; D000081247:CSK Tyrosine-Protein Kinase; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases
C115431:2-(4-(2-diethylaminoethoxy)phenylamino)-8-ethyl-6-phenyl-8H-pyrido(2,3-d)pyrimidin-7-one; D004791:Enzyme Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human