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Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in cftr, a gene encoding a PKA-regulated [Cl.sup.-] channel. The most common mutation results in a deletion of phenylalanine at position 508 ([DELTA]F508-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 [DELTA]F508-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 [DELTA]F508-CFTR-mediated [Cl.sup.-] 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 [DELTA]F508-CFTR and achieves single-channel activity similar to wild-type CFTR. The CFTR-actirating 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. high-throughput screening; human bronchial epithelia; [Cl.sup.-] channels: corrector; potentiator

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]

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]

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]

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

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.

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.