The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy.
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.
Aventis, Dagenham Research Centre, Essex, UK.
L M
LM
Mclay
F
F
Halley
J E
JE
Souness
J
J
McKenna
V
V
Benning
M
M
Birrell
B
B
Burton
M
M
Belvisi
A
A
Collis
A
A
Constan
M
M
Foster
D
D
Hele
Z
Z
Jayyosi
M
M
Kelley
C
C
Maslen
G
G
Miller
M C
MC
Ouldelhkim
K
K
Page
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S
Phipps
K
K
Pollock
B
B
Porter
A J
AJ
Ratcliffe
E J
EJ
Redford
S
S
Webber
B
B
Slater
V
V
Thybaud
N
N
Wilsher
D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D001682:Biological Availability; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; C431783:RPR 200765A; D014409:Tumor Necrosis Factor-alpha; D019363:Cytochrome P-450 CYP1A1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases