ABSTRACT
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be associated with dysfunctional airway epithelial ion transport, suggesting a role for CFTR in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, the identification and characterization of a high throughput screening hit 6 as a potentiator of mutant human F508del and wild-type CFTR channels is reported. The design, synthesis, and biological evaluation of compounds 7-33 to establish structure-activity relationships of the scaffold are described, leading to the identification of clinical development compound icenticaftor (QBW251) 33, which has subsequently progressed to deliver two positive clinical proofs of concept in patients with CF and COPD and is now being further developed as a novel therapeutic approach for COPD patients.
Subject(s)
Aminopyridines/chemistry , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Administration, Oral , Aminopyridines/metabolism , Aminopyridines/therapeutic use , Animals , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Deletion , Half-Life , Humans , Protein Binding , Pulmonary Disease, Chronic Obstructive/drug therapy , Rats , Rats, Sprague-Dawley , Solubility , Structure-Activity RelationshipABSTRACT
Combined photochemical arylation, "nuisance effect" (SN Ar) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out of control" in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SN Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.
Subject(s)
Benzene Derivatives/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Small Molecule Libraries/chemical synthesis , Benzene Derivatives/metabolism , Catalysis , Chemistry Techniques, Synthetic/methods , Coordination Complexes/chemistry , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/metabolism , Feasibility Studies , Humans , Palladium/chemistry , Proof of Concept Study , Protein Binding , Pyridines/chemical synthesis , Pyridines/metabolism , Pyrophosphatases/metabolism , Pyrrolidinones/chemical synthesis , Pyrrolidinones/metabolism , Small Molecule Libraries/metabolism , Nudix HydrolasesABSTRACT
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.