Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase.
The development of potent, orally bioavailable (in rat) and selective dihydroquinazolinone inhibitors of p38alpha MAP kinase is described. These analogues are hybrids of a pyridinylimidazole p38alpha inhibitor reported by Merck Research Laboratories and VX-745. Optimization of the C-5 phenyl and the C-7 piperidinyl substituents led to the identification of 15i which gave excellent suppression of TNF-alpha production in LPS-stimulated whole blood (IC(50)=10nM) and good oral exposure in rats (F=68%, AUCn PO=0.58 microM h).
Stelmach
John E
JE
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. john_stelmach@merck.com
Liu
Luping
L
Patel
Sangita B
SB
Pivnichny
James V
JV
Scapin
Giovanna
G
Singh
Suresh
S
Hop
Cornelis E C A
CE
Wang
Zhen
Z
Strauss
John R
JR
Cameron
Patricia M
PM
Nichols
Elizabeth A
EA
O'Keefe
Stephen J
SJ
O'Neill
Edward A
EA
Schmatz
Dennis M
DM
Schwartz
Cheryl D
CD
Thompson
Chris M
CM
Zaller
Dennis M
DM
Doherty
James B
JB
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases