A novel Pd-catalyzed cyclization reaction of ureas for the synthesis of dihydroquinazolinone p38 kinase inhibitors.
A series of potent p38 inhibitors based on the dihydroquinazoline scaffold was synthesized using a novel Pd-catalyzed cyclization reaction of aryl-benzyl ureas. Optimization of this compound class led to compound 20, which inhibits p38alpha in vitro with IC(50)=14 nM and is active in the mouse TNFalpha-release model.
Schlapbach
Achim
A
Novartis Institute for Biomedical Research, Arthritis and Bone Metabolism, Lichtstrasse, CH-4002, Basel, Switzerland. achim.schlapbach@pharma.novartis.com
Heng
Richard
R
Di Padova
Franco
F
D000818:Animals; D002384:Catalysis; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007854:Lead / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000138:chemical synthesis* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D011799:Quinazolines; D007854:Lead; D014508:Urea; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases