10008-12-5Relevant articles and documents
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Adams,Binder
, p. 2773,2774 (1941)
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Optimization of isochromanone based urotensin II receptor agonists
Lehmann, Fredrik,Currier, Erika A.,Olsson, Roger,Ma, Jian-Nong,Burstein, Ethan S.,Hacksell, Uli,Luthman, Kristina
experimental part, p. 4844 - 4854 (2010/08/06)
A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one (28) being the most potent compound showing an EC50-value of 51 nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present.
Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease: Secondary amide series
Reich, Siegfried H.,Melnick, Michael,Pino, Mark J.,Fuhry, Mary Ann M.,Trippe, Anthony J.,Appelt, Krzysztof,Davies II, Jay F.,Wu, Bor-Wen,Musick, Linda
, p. 2781 - 2794 (2007/10/03)
The design, synthesis, and crystallographic analysis of protein- inhibitor complexes is described for a novel series of nonpeptidic HIV protease (HIV Pr) inhibitors. Beginning with a cocrystal structure of a Phe- Pro peptidomimetic bound to the HIV Pr, design was initiated that resulted in the substituted 2-butanol compound 8 as the lead compound (K(i) = 24.5 μM, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, K(i) = 0.48 μM). These inhibitors were found to bind to the enzyme essentially as predicted on the basis of the original design hypothesis. Stereospecific synthesis of individual enantiomers confirmed the prediction of a binding preference for the S alcohol stereochemistry. Modest antiviral activity was demonstrated for several of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.