Bridged Piperazines and Piperidines as CCR1 Antagonists with Oral Activity in Models of Arthritis and Multiple Sclerosis

Laszlo Revesz; Birgit Bollbuck; Thomas Buhl; Janet Dawson; Roland Feifel; Richard Heng; Peter Hiestand; Helmut Sparrer; Achim Schlapbach; Rudolf Waelchli

doi:10.2174/157018006778631866

ISSN: 1570-1808
E-ISSN: 1875-628X

Bridged Piperazines and Piperidines as CCR1 Antagonists with Oral Activity in Models of Arthritis and Multiple Sclerosis
Authors: Laszlo Revesz¹, Birgit Bollbuck², Thomas Buhl³, Janet Dawson⁴, Roland Feifel⁵, Richard Heng⁶, Peter Hiestand⁷, Helmut Sparrer⁸, Achim Schlapbach⁹ and Rudolf Waelchli¹⁰
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¹ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ² Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ³ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ⁴ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ⁵ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ⁶ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ⁷ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ⁸ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ⁹ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland. ¹⁰ Novartis Institutes for BioMedical Research, WSJ 507-601, CH-4002 Basel, Switzerland.
Source: Letters in Drug Design & Discovery, Volume 3, Issue 10, Dec 2006, p. 689 - 694
DOI: https://doi.org/10.2174/157018006778631866
- Available online: 01 Dec 2006

Abstract

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.

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2006-12-01

2025-12-12

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Article Type: Research Article

Keyword(s): Antagonist; Bridged piperazine; CCR1; Multiple sclerosis; Rheumatoid arthritis

Bridged Piperazines and Piperidines as CCR1 Antagonists with Oral Activity in Models of Arthritis and Multiple Sclerosis

Abstract

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