ABSTRACT
[This corrects the article DOI: 10.1021/acsmedchemlett.7b00157.].
ABSTRACT
Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.
ABSTRACT
Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.
Subject(s)
Indolizines/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Administration, Oral , Animals , CHO Cells , Cricetinae , Cricetulus , Dermatitis, Contact/drug therapy , Disease Models, Animal , Drug Evaluation, Preclinical , Eosinophils/drug effects , Eosinophils/metabolism , Half-Life , Humans , Hypersensitivity/drug therapy , Indolizines/pharmacokinetics , Indolizines/therapeutic use , Mice , Mice, Inbred BALB C , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/genetics , Receptors, Prostaglandin/metabolism , Structure-Activity Relationship , Th2 Cells/immunology , Th2 Cells/metabolismABSTRACT
High throughput screening identified a 7-azaindole-3-acetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a highly selective compound with good functional potency for inhibition of human eosinophil shape change in whole blood and oral bioavailability in the rat.
Subject(s)
Acetates/chemistry , Anti-Inflammatory Agents/chemistry , Pyridines/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Administration, Oral , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Eosinophils/drug effects , Eosinophils/immunology , Humans , Microsomes, Liver/metabolism , Permeability , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity RelationshipABSTRACT
High throughput screening identified a phenoxyacetic acid scaffold as a novel CRTh2 receptor antagonist chemotype, which could be optimised to furnish a compound with functional potency for inhibition of human eosinophil shape change and oral bioavailability in the rat.
