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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Pamapimod, a Novel p38 Mitogen-Activated Protein Kinase Inhibitor: Preclinical Analysis of Efficacy and Selectivity

Departments of Cellular and Molecular Pharmacology (R.J.H., D.P., R.T.S., M.W., K.W.S., K.-c.C., D.A., A.M.M., S.L.P., B.R.W.), in Vivo Pharmacology (K.D., D.L., Y.-N.K., R.T.R., J.D.P.), Biochemical Pharmacology (E.P.), Pathology (T.S.Z.), and Medicinal Chemistry (D.M.G.), Roche Pharmaceuticals, Palo Alto, California; Kennedy Institute of Rheumatology, Imperial College, London, United Kingdom (C.L.); and Immunology Research, Biogen Idec, Cambridge, Massachusetts (A.A.M.)

P38 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 p38 and p38β enzymatic activity, with IC₅₀ values of 0.014 ± 0.002 and 0.48 ± 0.04 µM, respectively. There was no activity against p38 or p38 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 NH₂-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC₅₀, 0.06 µM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production by monocytes, interleukin (IL)-1β production in human whole blood, and spontaneous TNF production by synovial explants from RA patients. LPS- and TNF-stimulated production of TNF 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 p38 with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.

Address correspondence to: Dr. Ronald J. Hill, Inflammation Discovery, Roche Pharmaceuticals, 3431 Hillview Ave., Palo Alto, CA 94304. E-mail: ronald.hill{at}roche.com