Soluble 2-substituted aminopyrido[2,3-d]pyrimidin-7-yl ureas. Structure-activity relationships against selected tyrosine kinases and exploration of in vitro and in vivo anticancer activity
Mc. Schroeder et al., Soluble 2-substituted aminopyrido[2,3-d]pyrimidin-7-yl ureas. Structure-activity relationships against selected tyrosine kinases and exploration of in vitro and in vivo anticancer activity, J MED CHEM, 44(12), 2001, pp. 1915-1926
continuing our search for medicinal agents to treat proliferative diseases,
we have discovered 2-substituted aminopyrido[2,3-d]pyrimidin-7-yl ureas as
a novel class of soluble, potent, broadly active tyrosine kinase (TK) inhi
bitors. An efficient route was developed that enabled the synthesis of a wi
de variety of analogues with substitution on several positions of the templ
ate. From the lead structure 1, several series of analogues were made that
examined the C-6 aryl substituent, a variety of water solublizing substitut
ents at the C-2 position, and urea or other acyl functionality at the N-7 p
osition. Compounds of this series were competitive with ATP and displayed s
ubmicromolar to low nanomolar potency against a panel of TKs, including rec
eptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGF
r;) and nonreceptor (c-Src) classes. Several of the most potent compounds d
isplayed submicromolar inhibition of PDGF-mediated receptor autophosphoryla
tion in rat aortic vascular smooth muscle cells and low micromolar inhibiti
on of cellular growth in five human tumor cell lines. One of the more thoro
ughly evaluated members, 32, with IC50 values of 0.21 muM (PDGFr), 0.049 mu
M (bFGFr), and 0.018 muM (c-Src), was evaluated in in vivo studies against
a panel of five human tumor xenografts, with known and/or inferred dependen
ce on the EGFr, PDGFr, and c-Src TKs. Compound 32 produced a tumor growth d
elay of 14 days against the Cole-205 colon xenograft model.