PMID: 11906290Mar 22, 2002Paper

Synthesis and structure-activity relationships of 3-aryloxindoles: a new class of calcium-dependent, large conductance potassium (maxi-K) channel openers with neuroprotective properties

Journal of Medicinal Chemistry
Piyasena HewawasamNicholas A Meanwell

Abstract

A series of 3-aryloxindole derivatives were synthesized and evaluated as activators of the cloned maxi-K channel mSlo expressed in Xenopus laevis oocytes using electrophysiological methods. The most promising maxi-K openers to emerge from this study were (+/-)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one ((+/-)-8c) and its 3-des-hydroxy analogue (+/-)-11b. The individual enantiomers of (+/-)-8c were synthesized, and the maxi-K channel-opening properties were shown to depend on the absolute configuration of the single stereogenic center with the efficacy of (-)-8c superior to that of both (+)-8c and the racemic mixture when evaluated at a concentration of 20 microM. Racemic 11b exhibited greater efficacy than either the racemic 8c or the more active enantiomer in the electrophysiological evaluation. In vitro metabolic stability studies conducted with (+/-)-8c and (+/-)-11b in rat liver S9 microsomal fractions revealed significant oxidative degradation with two hydroxylated metabolites observed by liquid chromatography/mass spectrometry for each compound in addition to the production of 8c from 11b. The pharmacokinetic properties of (+/-)-8c and (+/-)-11b were determined in rats as a prelu...Continue Reading

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Citations

Mar 23, 2002·Bioorganic & Medicinal Chemistry Letters·Piyasena HewawasamJohn E Starrett
Aug 8, 2009·Chemical Communications : Chem Comm·Kun JiangYing-Chun Chen
Apr 20, 2004·Assay and Drug Development Technologies·Ashutosh S PariharChar-Chang Shieh
Sep 10, 2014·Life Sciences·Patricia D FernandesAngelo C Pinto
Jun 2, 2005·Expert Opinion on Investigational Drugs·Valentin K Gribkoff, Raymond J Winquist
Jun 10, 2016·The Journal of Organic Chemistry·De-Long KongLi Liu
Dec 20, 2005·Bioorganic & Medicinal Chemistry Letters·Eoin C PowerDavid C H Benton
Apr 6, 2006·Angewandte Chemie·Ryo ShintaniTamio Hayashi
Apr 4, 2015·Biological Chemistry·Marina DiskowskiInga Hänelt
Mar 10, 2020·Chemistry : a European Journal·Koichi OkamotoHideki Yorimitsu
Feb 10, 2004·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Domenico TricaricoDiana Conte Camerino
Aug 30, 2003·Organic & Biomolecular Chemistry·Ludivine ZouteDominique Cahard
Jul 28, 2012·Chemistry : a European Journal·Chuan WangDieter Enders
Sep 24, 2014·Organic & Biomolecular Chemistry·Jinsen ChenJin Zhu
Jul 12, 2008·The Journal of Organic Chemistry·J Mikael Hillgren, Stephen P Marsden
Mar 7, 2008·Organic Letters·Matthew J Durbin, Michael C Willis
Aug 15, 2006·Bioorganic & Medicinal Chemistry·Toshihiko TashimaTomohiko Ohwada
Oct 23, 2019·The Journal of Organic Chemistry·Atanu BhaumikBhoopendra Tiwari

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