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.
Pfizer Global Research and Development, St. Louis, MO 63017, USA. jkwalker24@sbcglobal.net
John K
JK
Walker
Shaun R
SR
Selness
Rajesh V
RV
Devraj
Michael E
ME
Hepperle
Win
W
Naing
Huey
H
Shieh
Ravi
R
Kurambail
Syaulan
S
Yang
Daniel L
DL
Flynn
Alan G
AG
Benson
Dean M
DM
Messing
Tom
T
Dice
Tina
T
Kim
R J
RJ
Lindmark
Joseph B
JB
Monahan
Joseph
J
Portanova
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