The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy

Autor: Nicola E. Wilsher, Andrew J. Ratcliffe, Brenda J. Burton, Collis Alan John, Maria G. Belvisi, Iain Mcfarlane Mclay, Chris Maslen, Simon Phipps, Martyn Foster, Kenneth Page, Michael F. Kelley, Bryan Slater, Stephen E Webber, Jayyosi Zaid, Kenneth Pollock, V. Benning, Alex Constan, Elisabeth J. Redford, David J Hele, Jeffrey Mckenna, Glen K. Miller, Véronique Thybaud, Barry Porter, Frank Halley, Marie-Claude Ouldelhkim, Mark A. Birrell, John E. Souness
Rok vydání: 2001
Předmět:
Lipopolysaccharides
Inflammatory arthritis
medicine.medical_treatment
Clinical Biochemistry
Administration
Oral
Biological Availability
Pharmaceutical Science
Arthritis
Pharmacology
p38 Mitogen-Activated Protein Kinases
Biochemistry
Monocytes
Rats
Sprague-Dawley
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Drug Stability
In vivo
Drug Discovery
Cytochrome P-450 CYP1A1
medicine
Animals
Humans
Enzyme Inhibitors
Molecular Biology
Dose-Response Relationship
Drug
biology
Tumor Necrosis Factor-alpha
Chemistry
Mesylate
Organic Chemistry
Imidazoles
medicine.disease
Rats
Disease Models
Animal
Cytokine
Enzyme inhibitor
Antirheumatic Agents
Enzyme Induction
Rheumatoid arthritis
Immunology
biology.protein
Molecular Medicine
Female
Tumor necrosis factor alpha
Mitogen-Activated Protein Kinases
Zdroj: Bioorganic & Medicinal Chemistry. 9:537-554
ISSN: 0968-0896
DOI: 10.1016/s0968-0896(00)00331-x
Popis: RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.
Databáze: OpenAIRE
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