Chapter Ten - Recent Advances in the Discovery and Development of CCR1 Antagonists

• Autores: Penglie Zhang, Daniel J. Dairaghi, Juan C. Jaen, Jay P. Powers
• Localización: Annual reports in medicinal chemistry, ISSN 0065-7743, Vol 48, 2013, págs. 133-147
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • Abstract CCR1 and its chemokine ligands are implicated in multiple human diseases, including rheumatoid arthritis, multiple sclerosis, and multiple myeloma and associated osteolytic bone disease. There has been an intense interest in the discovery and development of small molecule CCR1 antagonists, of which nine have advanced into human clinical trials. While the clinical experience of earlier compounds has been mixed, CCX354 has demonstrated proof-of-concept in a recently completed Phase 2 RA trial. As CCR1 antagonists with more favorable preclinical profiles in potency, PK, and safety continue to emerge, sufficient receptor coverage under physiological conditions might be conveniently achieved without safety concerns so that various clinical indications can be tested unambiguously. The outcome of the ongoing RA trial with BMS-817399, if positive, will provide additional support for targeting CCR1 as an effective therapy in inflammatory diseases.