A series of triarylethanolamine inhibitors of the Kv1.5 potassium channel have been prepared and evaluated for their effects in vitro and in vivo. The structure–activity relationship (SAR) studies described herein led to the development of potent, selective and orally active inhibitors of Kv1.5.

The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.

A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTClass III Antiarrhythmic Activity in Vivo by Selective Blockade of the Slowly Activating Cardiac Delayed Rectifier Potassium Current IKs by (R)-2-(2,4- Trifluoromethyl)-N-[2-oxo-5-phenyl- 1-(2,2,2-trifluoroethyl)-2,3-dihydro- 1H-benzo[e][1,4]diazepin-3-yl]acetamideHarold G. Selnick, Nigel J. Liverton, John J. Baldwin, John W. Butcher, David A. Claremon, Jason M. Elliott, Roger M. Freidinger, Stella A. King, Brian E. Libby, Charles J. McIntyre, David A. Pribush, David C. Remy, Garry R. Smith, Andrew J. Tebben, Nancy K. Jurkiewicz, Joseph J. Lynch, Joseph J. Salata, Michael C. Sanguinetti, Peter K. S. Siegl, Donald E. Slaughter, and Kamlesh VyasView Author Information Departments of Medicinal Chemistry, Pharmacology, and Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486 Cite this: J. Med. Chem. 1997, 40, 24, 3865–3868Publication Date (Web):November 21, 1997Publication History Received4 August 1997Published online21 November 1997Published inissue 1 November 1997https://pubs.acs.org/doi/10.1021/jm970517uhttps://doi.org/10.1021/jm970517urapid-communicationACS PublicationsCopyright © 1997 American Chemical SocietyRequest reuse permissionsArticle Views644Altmetric-Citations86LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Amides,Azides,Molecular structure,Potassium,Receptors Get e-Alerts

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the alpha-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.