- Visible Light-Mediated [2 + 2] Cycloaddition Reactions of 1,4-Quinones and Terminal Alkynes
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A single-step synthesis of 4-hydroxy-functionalized bi-aryl and aryl/alkyl ketones via oxidative coupling of terminal alkynes with benzoquinones is reported. Furthermore, with naphthoquinones, owing to the cross-resonance of carbonyl with the aromatic ring, alkene-alkyne cycloaddition is more favored to give four-membered carbocyclic adducts, thereby precluding the requirement of preactivated alkynes.
- Sultan, Shaista,Bhat, Muneer-Ul-Shafi,Rizvi, Masood Ahmad,Shah, Bhahwal Ali
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p. 8948 - 8958
(2019/08/12)
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- Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel
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We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [3H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.
- Yu, Zhiyi,Van Veldhoven, Jacobus P.D.,'T Hart, Ingrid M.E.,Kopf, Adrian H.,Heitman, Laura H.,Ijzerman, Adriaan P.
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- 4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention
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H3 receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H 3 receptors, with Ki values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)- methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H3 receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H3 receptor antagonists for the treatment of cognitive dysfunction.
- Cowart, Marlon,Faghih, Ramin,Curtis, Michael P.,Gfesser, Gregory A.,Bennani, Youssef L.,Black, Lawrence A.,Pan, Liping,Marsh, Kennan C.,Sullivan, James P.,Esbenshade, Timothy A.,Fox, Gerard B.,Hancock, Arthur A.
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