Piperidine-based heterocyclic oxalyl amides as potent p38 alpha MAP kinase inhibitors.
The design and synthesis of a new class of p38alpha MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38alpha enzymatic and cell-based cytokine TNFalpha production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.
Mavunkel
Babu J
BJ
Department of Medicinal Chemistry and Biology, Scios, Inc, 6500 Paseo Padre Parkway, Fremont, CA 94555, USA.
Perumattam
John J
JJ
Tan
Xuefei
X
Luedtke
Gregory R
GR
Lu
Qing
Q
Lim
Don
D
Kizer
Darin
D
Dugar
Sundeep
S
Chakravarty
Sarvajit
S
Xu
Yong-jin
YJ
Jung
Joon
J
Liclican
Albert
A
Levy
Daniel E
DE
Tabora
Jocelyn
J
D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010070:Oxalates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000577:Amides; D006571:Heterocyclic Compounds; D010070:Oxalates; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C032727:piperidine; D048308:Mitogen-Activated Protein Kinase 14