Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase.
Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
Walker
John K
JK
Pfizer Global Research and Development, St. Louis, MO 63017, USA. jkwalker24@sbcglobal.net
Selness
Shaun R
SR
Devraj
Rajesh V
RV
Hepperle
Michael E
ME
Naing
Win
W
Shieh
Huey
H
Kurambail
Ravi
R
Yang
Syaulan
S
Flynn
Daniel L
DL
Benson
Alan G
AG
Messing
Dean M
DM
Dice
Tom
T
Kim
Tina
T
Lindmark
R J
RJ
Monahan
Joseph B
JB
Portanova
Joseph
J
D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C545840:SD 0006; D048051:p38 Mitogen-Activated Protein Kinases