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
A library of chemokine antagonists has been synthesized using a combination of solid and solution-phase chemistry. Structures of known chemokine antagonists were used to produce a pharmacophore which served to guide monomer selection. Several combinations of monomers have resulted in providing novel chemokine antagonists which in some cases display dual chemokine receptor antagonism.
Subject(s)
Chemokines/antagonists & inhibitors , Drug Design , Small Molecule Libraries , Animals , Cell Line , Cricetinae , CricetulusABSTRACT
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.
Subject(s)
Acetates/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Animals , Biological Availability , Eosinophils/drug effects , Humans , Rats , Structure-Activity RelationshipABSTRACT
In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms.