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Quinolinone-3-carboxamide 1, a novel CFTR potentiator,was discovered using high-throughput screening in NIH-3T3 cells expressingthe F508del-CFTR mutation. Extensive medicinal chemistry and iterativestructure–activity relationship (SAR) studies to evaluate potency,selectivity, and pharmacokinetic properties resulted in the identificationof N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(VX-770, 48, ivacaftor), an investigational drug candidateapproved by the FDA for the treatment of CF patients 6 years of ageand older carrying the G551D mutation. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC50, 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770. an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (Po) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl- secretion in cultured human CF bronchial epithelia (HBE) carrying the G551 D gating mutation on one allele and the F508del processing mutation on the other allele by ≈10-fold. to ≈50% of that observed in HBE isolated from individuals without CF. Furthermore. VX-770 reduced excessive Na+ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway. [ABSTRACT FROM AUTHOR]

Presents information on a study which synthesized eight members of a family of fluorinated tin hydrides for radical reactions. Methodology; Results and discussion; Conclusions.

Presents a fluorous synthesis approach in which organic molecules are rendered soluble in fluorocarbon solvents by attachment of a suitable fluorocarbon group. Properties of fluorocarbon solvents; The achievement of simple separations of organic reaction mixtures without chromatography; Implications for synthesis of individual pure organic compounds.

Describes the palladium-catalyzed heteroarylation of 2- and 3-indolyzinc derivatives. Method for the preparation of (2-pyrisdyl)indoles; Demonstration of the potential of (2-pyridyl)indoles in the alkaloid synthesis; Study of the Pummerer cyclizations.

Examines the configurational stability of 2-(2-piperidyl)indoles. Conversion into tetracyclic ketone; Epimerization at the C-4 position; Syntheses of Strychnos; Stereochemical assignments of piperidines.

Abstract: A direct synthesis of trimethyl(2-phenoxyethyl)silanes from the corresponding aromatic fluorides and 2-(trimethylsilyl)ethanol was developed. A variety of substituents were tolerated and a substitution reaction using 1-bromo-3-chloro-5-fluorobenzene was demonstrated. [Copyright &y& Elsevier]

Describes the synthesis of a new fluorous allylstannane, (C6F13CH2CH2)3SnCH2-CH=CH2. Demonstration that the fluorous allylstannane's thermal reactions with aldehydes are roughly comparable to the reactions with the standard reagent Bu3SnCh2CH=CH2; Methodology used in study; Study's findings on fluorous allylstannane.

Investigates the preparation and reactions of 1-(tert-Butyldimethylsilyl)-3-lithioindole. Analysis of the regioselective synthesis of 3-substituted indoles; Nucleophilic character of 3-position in simple indoles or in indolylmagnesium halides; Reactivity with electrophilic alkylating.

The addition of α-deprotonated nitriles to azaheterocycles followed by rearomatization is described. A simple two-step, one-pot procedure for the sequence is also presented. [ABSTRACT FROM AUTHOR]

The article presents chemical equations related to the article "Addition of α-Lithiated Nitriles to Azaheterocycles" by C. Anderson, J. Moreno and S. Hadida, published in the periodical "Synlett" in 2014.

Abstract: Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (K i =30pM, IC50 =1nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties. [Copyright &y& Elsevier]

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated Cl channel. The most common mutation results in a deletion of phenylalanine at position 508 (ΔF508-CFTR) that impairs protein folding, trafficking, and channel gating in epithelial cells. In the airway, these defects alter salt and fluid transport, leading to chronic infection, inflammation, and loss of lung function. There are no drugs that specifically target mutant CFTR, and optimal treatment of CF may require repair of both the folding and gating defects. Here, we describe two classes of novel, potent small molecules identified from screening compound libraries that restore the function of ΔF508-CFTR in both recombinant cells and cultures of human bronchial epithelia isolated from CF patients. The first class partially corrects the trafficking defect by facilitating exit from the endoplasmic reticulum and restores ΔF508-CFTR-mediated Cl- transport to more than 10% of that observed in non-CF human bronchial epithelial cultures, a level expected to result in a clinical benefit in CF patients. The second class of compounds potentiates cAMP-mediated gating of ΔF508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-activating effects of the two mechanisms are additive and support the rationale of a drug discovery strategy based on rescue of the basic genetic defect responsible for CF. [ABSTRACT FROM AUTHOR]