Design and synthesis of piperazine-indole p38 alpha MAP kinase inhibitors with improved pharmacokinetic profiles.
Derivatives of the 4-fluorobenzyl dimethylpiperazine-indole class of p38alpha MAP kinase inhibitors are described. Biological evaluation of these compounds focused on maintaining activity while improving pharmacokinetic (PK) properties. Improved properties were observed for structures bearing substitutions on the benzylic methylene.
Tan
Xuefei
X
Department of Medicinal Chemistry and Biology, Scios inc, 6500 Paseo Padre Parkway, Fremont, CA 94555, United States. Xuefei827@gmail.com
Tester
Richland W
RW
Luedtke
Gregory R
GR
Chakravarty
Sarvajit
S
Mavunkel
Babu J
BJ
Perumattam
John J
JJ
Lu
Qing
Q
Nashashibi
Imad
I
Jung
Joon
J
Hu
Jie
J
Liclican
Albert
A
Almirez
Ramona
R
Tabora
Jocelyn
J
Tran
Vinh
V
Laney
Maureen
M
Levy
Daniel E
DE
Dugar
Sundeep
S
D000818:Animals; D004285:Dogs; D015195:Drug Design; D000882:Haplorhini; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D017433:Protein Structure, Secondary; D051381:Rats
D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000077489:Piperazine; D048308:Mitogen-Activated Protein Kinase 14