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
A series of novel benzimidazole derivatives has been designed via a scaffold morphing approach based on known calcilytics chemotypes. Subsequent lead optimisation led to the discovery of penta-substituted benzimidazoles that exhibit attractive in vitro and in vivo calcium-sensing receptor (CaSR) inhibitory profiles. In addition, synthesis and structure-activity relationship data are provided.
Subject(s)
Benzimidazoles/pharmacology , Receptors, Calcium-Sensing/antagonists & inhibitors , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Models, Molecular , Structure-Activity RelationshipABSTRACT
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
The enantiomers of two different derivatives of tert-leucine were separated by continuous chromatography on chiral stationary phases applying the simulated moving bed technique. About 1 kg of racemic N-carbobenzoxy-tert-leucine was resolved on the cellulose-based phase Chiralcel OD using a mixture of heptane/ethanol and 0.1% of trifluoroacetic acid modifier as the mobile phase, while 520 g of the N-Boc-tert-leucine-benzylester was resolved on the amylose-based phase Chiralpak AD with a mixture of heptane/2-propanol as the mobile phase. In both instances the corresponding enantiomers were obtained in high yield and high optical purity.
