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.
In 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) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 1, several series of analogues were made that examined the C-6 aryl substituent, a variety of water solublizing substitutents at the C-2 position, and urea or other acyl functionality at the N-7 position. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr;) and nonreceptor (c-Src) classes. Several of the most potent compounds displayed submicromolar inhibition of PDGF-mediated receptor autophosphorylation in rat aortic vascular smooth muscle cells and low micromolar inhibition of cellular growth in five human tumor cell lines. One of the more thoroughly evaluated members, 32, with IC50 values of 0.21 microM (PDGFr), 0.049 microM (bFGFr), and 0.018 microM (c-Src), was evaluated in in vivo studies against a panel of five human tumor xenografts, with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs. Compound 32 produced a tumor growth delay of 14 days against the Colo-205 colon xenograft model.
Schroeder
M C
MC
Departments of Chemistry, Cancer Research, and Vascular and Cardiac Diseases, Pfizer Global Research & Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. mel.schroeder@pfizer.com
Hamby
J M
JM
Connolly
C J
CJ
Grohar
P J
PJ
Winters
R T
RT
Barvian
M R
MR
Moore
C W
CW
Boushelle
S L
SL
Crean
S M
SM
Kraker
A J
AJ
Driscoll
D L
DL
Vincent
P W
PW
Elliott
W L
WL
Lu
G H
GH
Batley
B L
BL
Dahring
T K
TK
Major
T C
TC
Panek
R L
RL
Doherty
A M
AM
Showalter
H D
HD
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005910:Glioma; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019061:src-Family Kinases
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D014508:Urea; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human