ABSTRACT
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Subject(s)
Anti-Inflammatory Agents/chemistry , Isoindoles/chemistry , Receptors, Prostaglandin E, EP4 Subtype/agonists , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Blood Cells/cytology , Blood Cells/drug effects , Blood Cells/metabolism , Dinoprostone/chemistry , Dinoprostone/therapeutic use , Drug Evaluation, Preclinical , Half-Life , Humans , Inhibitory Concentration 50 , Isoindoles/pharmacokinetics , Isoindoles/therapeutic use , Lipopolysaccharides/pharmacology , Pain/drug therapy , Pain/pathology , Pain/veterinary , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Rats , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Subject(s)
Benzimidazoles/pharmacology , Drug Discovery , PPAR gamma/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Molecular Structure , PPAR gamma/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.