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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

A study on the organic chemistry of tin and tin hydride radical chemistry reports on the results of the synthesis and analysis of eight members of a new family of highly fluorinated tin hydrides as reagents for radical reactions. It provides some of the first detailed information on how the nature and composition of fluorous chains affects the reactivity and solubility of fluorous reagents. Experimental methodology and results are presented.

A series of (2-pyridyl)indoles was synthesized from the palladium(0)-mediated reaction of (1-(tert-nutyldimethylsilyl)-3- indolyl)zinc chloride and (1-(benzenesulfonyl)-2-indolyl)zinc chloride. The resulting products were utilized for the synthesis of the indolo[2,3-alpha]quinolizidine system via the stereoselective hydrogenation of thge pyridine ring followed by electrophilic cyclization in the indole 3-position.

The cyclization of pure all-cis 3-(2-piperidyl)indole was carried out to examine epimerization reactions at the C-2 and C-4 positions of the piperidine ring. Specifically, the piperidine-4-carboxylic acids obtained from the saponification of the 3-(2-piperidyl)indoles were reesterified with excess diazomethane. The results revealed that epimerization occurs at the C-2 position of the piperidine during alkaline hydrolysis of the ester.

The use of supercritical CO2 as a reaction solvent has been limited, and a solution could be to use radical reactions that proceed well in nonpolar solvents. The simple reduction of bromoadamantane to adamantane, conducting radical reactions by initial pressurization to 850 psig, was investigaed. Tris(perfluorohexylethyl)tin hydride was soluble under reaction conditions, although a mixture with tributyltin hydride was not homogenous.

The preparation and characterization of tris 2-(perfluorohexyl)ethyl tin hydride as a fluorous agent in combinatorial synthesis using organic substrates is discussed. The tin hydride was obtained from 2-perfluorohexyl-1-iodoethane via a series of steps culminating in reduction with lithium aluminum hydride in ether. To enable its efficient implementation, a homogeneous reaction medium, a benzotrifluoride otherwise known as (trifluoromethyl)toluene, was employed.

Halogen-metal exchange from the corresponding 3-bromoderivative yields 1-(tert-butyldimethylsilyl)-3-lithioindole which reacts with electrophiles to form 3-substituted indoles. The N-silyl-3-lithioindole is of value in the synthesis of 3-substituted indoles due to the absence of ring fragmentation and rearrangement and the easy elimination of the protecting group.

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]

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.

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.

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]