ABSTRACT
This report describes the design and synthesis of a series of CCR2 antagonists incorporating novel non-aryl/heteroaryl RHS (right hand side) motifs. Previous SAR in the area has suggested an aryl/heteroaryl substituent as a necessary structural feature for binding to the CCR2 receptor. Herein we describe the SAR with regards to potency (binding to hCCR2), dofetilide activity and metabolic stability (in vitro HLM) for this series. The resulting outcome was the identification of compounds with excellent properties for the investigation of the role of CCR2 in disease.
Subject(s)
Drug Design , Receptors, CCR2/antagonists & inhibitors , Binding Sites , Models, Molecular , Structure-Activity RelationshipABSTRACT
We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35-45mg BID and a CV-TI=3800-fold.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacology , Receptors, CCR2/agonists , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Biological Assay , Humans , Inhibitory Concentration 50 , Microsomes/drug effects , Microsomes/metabolism , Molecular Structure , Piperazines/pharmacokinetics , Protein Binding/drug effects , Pyridazines/pharmacokinetics , Receptors, CCR2/blood , Structure-Activity RelationshipABSTRACT
We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.
