title: Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase.
abstract: The p38 mitogen activated protein kinase (MAPK) is a key signaling molecule that plays a crucial role in the progression of various inflammatory diseases such as rheumatoid arthritis (RA), asthma and chronic obstructive pulmonary disease. The objective of the present study was to evaluate the anti-inflammatory activity of a p38 MAPK inhibitor, AW-814141. AW-814141 inhibited enzymatic activity of recombinant p38-alpha and beta isoforms with IC(50) value of 100nM and 158nM, respectively. AW-814141 also inhibited the release of tumor necrosis factor (TNF)-alpha by lipopolysaccharide (LPS) treated human peripheral blood mononuclear cells with an IC(50) value of 212nM and demonstrated selectivity against a panel of few kinases. Oral administration of AW-814141 (10mpk) in LPS-injected mice resulted in a significant reduction in TNF-alpha production in the circulation. In a carrageenan-induced rat paw edema model and collagen-induced arthritis model (CIA), AW-814141 dose dependently inhibited paw swelling. In different in vivo efficacy models, efficacy of AW-814141 was found to be better as compared to the reference compounds (Vx-745 and BIRB-796). This study demonstrated that AW-814141 is a novel p38 MAPK inhibitor and it displays promising in vitro and in vivo anti-inflammatory activities and can be used for the treatment of rheumatoid arthritis.
authors.affiliation: Department of Pharmacology, Ranbaxy Research Laboratories, Gurgaon, 122001-Haryana India. p.chopra@ranbaxy.com
authors.forename: Puneet
authors.initials: P
authors.lastname: Chopra
authors.forename: Onkar
authors.initials: O
authors.lastname: Kulkarni
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Malini
authors.initials: M
authors.lastname: Bajpai
authors.forename: Vijay
authors.initials: V
authors.lastname: Kanoje
authors.forename: Manish
authors.initials: M
authors.lastname: Banerjee
authors.forename: Vimal
authors.initials: V
authors.lastname: Bansal
authors.forename: Senthil
authors.initials: S
authors.lastname: Visaga
authors.forename: Mou
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Tridib
authors.initials: T
authors.lastname: Chaira
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Shirumalla
authors.forename: Ashwani Kumar
authors.initials: AK
authors.lastname: Verma
authors.forename: Sunanda G
authors.initials: SG
authors.lastname: Dastidar
authors.forename: Geeta
authors.initials: G
authors.lastname: Sharma
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D002351:Carrageenan; D016923:Cell Death / Q000187:drug effects; D003094:Collagen; D016207:Cytokines / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics
chemical_list: C550460:2-(hexahydrocyclopenta(c)pyrrol-2-ylamino)-8-methyl-6-o-tolyl-8H-pyrido(2,3-d)pyrimidine-7-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases