Bridged Piperazines and Piperidines as CCR1 Antagonists with Oral Activity in Models of Arthritis and Multiple Sclerosis
CCR1 antagonists were prepared by coupling bridged piperazines and bridged piperidines with 2- acetylamino-4-chloro-5-methoxy cinnamic acid. Compound 2 of the series showed the desired equal potency against human, mouse and rat CCR1 (IC50= 20; 22; 28nM), exhibited a superior pharmacokinetic profile and inhibited the clinical grades in rat acute experimental autoimmune encephalomyelitis and knee swelling in rat antigen induced arthritis at doses of 2 x 30 and 2 x 15 mg/kg p.o.
Keywords: Rheumatoid arthritis, Multiple sclerosis, CCR1, Antagonist, Bridged piperazine
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