Potent quinoxaline-based inhibitors of PDGF receptor tyrosine kinase activity. Part 2: the synthesis and biological activities of RPR127963 an orally bioavailable inhibitor.
RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.
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Wei
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Aventis Pharmaceuticals, Route 202/206, Brigdewater, NJ 08807, USA.
Myers
Michael R
MR
Hanney
Barbara
B
Spada
Alfred P
AP
Bilder
Glenda
G
Galzcinski
Helen
H
Amin
Dilip
D
Needle
Saul
S
Page
Ken
K
Jayyosi
Zaid
Z
Perrone
Mark H
MH
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002455:Cell Division / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013552:Swine
D004791:Enzyme Inhibitors; D011810:Quinoxalines; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor