title: Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).
abstract: A new class of potent kinase inhibitors selective for mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK-2) for the treatment of rheumatoid arthritis has been prepared and evaluated. These inhibitors have IC50 values as low as 10 nM against the target and have good selectivity profiles against a number of kinases including CDK2, ERK, JNK, and p38. These MK-2 inhibitors have been shown to suppress TNFalpha production in U397 cells and to be efficacious in an acute inflammation model. The structure-activity relationships of this series, the selectivity for MK-2 and their activity in both in vitro and in vivo models are discussed. The observed selectivity is discussed with the aid of an MK-2/inhibitor crystal structure.
authors.affiliation: Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, USA. david.r.anderson@pfizer.com
authors.forename: David R
authors.initials: DR
authors.lastname: Anderson
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Meyers
authors.forename: William F
authors.initials: WF
authors.lastname: Vernier
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Mahoney
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: Nicole
authors.initials: N
authors.lastname: Caspers
authors.forename: Gennadiy I
authors.initials: GI
authors.lastname: Poda
authors.forename: John F
authors.initials: JF
authors.lastname: Schindler
authors.forename: David B
authors.initials: DB
authors.lastname: Reitz
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mourey
mesh_terms: D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020298:U937 Cells; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000099190:MAP-Kinase-Activated Kinase 2