title: Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity.
abstract: P38alpha is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. There was no activity against p38delta or p38gamma isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH(2)-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC(50), 0.06 microM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha production by monocytes, interleukin (IL)-1beta production in human whole blood, and spontaneous TNFalpha production by synovial explants from RA patients. LPS- and TNFalpha-stimulated production of TNFalpha and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Roche Pharmaceuticals, Palo Alto, CA 94304, USA. ronald.hill@roche.com
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
authors.forename: Karim
authors.initials: K
authors.lastname: Dabbagh
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.forename: Ching
authors.initials: C
authors.lastname: Li
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Suttmann
authors.forename: Mary
authors.initials: M
authors.lastname: Welch
authors.forename: Eva
authors.initials: E
authors.lastname: Papp
authors.forename: Kyung W
authors.initials: KW
authors.lastname: Song
authors.forename: Kung-Ching
authors.initials: KC
authors.lastname: Chang
authors.forename: David
authors.initials: D
authors.lastname: Leaffer
authors.forename: Yong-Nam
authors.initials: YN
authors.lastname: Kim
authors.forename: Richard T
authors.initials: RT
authors.lastname: Roberts
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.forename: Dee
authors.initials: D
authors.lastname: Aud
authors.forename: Joseph
authors.initials: J
authors.lastname: Dal Porto
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Manning
authors.forename: Stanford L
authors.initials: SL
authors.lastname: Peng
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wong
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D007674:Kidney Diseases / Q000517:prevention & control; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010024:Osteoporosis / Q000517:prevention & control; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
chemical_list: D053583:Interleukin-1beta; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C533858:pamapimod