- Identification of aryl sulfonamides as novel and potent inhibitors of NaV1.5
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We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of NaV1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT-3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective in shortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide NaV inhibitors that bind to the channel voltage sensors, these NaV1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.
- Bichler, Paul,Chang, Elaine,Cohen, Charles J.,Dean, Richard,Dehnhardt, Christoph M.,Empfield, James R.,Goodchild, Samuel J.,Hussainkhel, Angela,Jia, Qi,Johnson, J. P.,Khakh, Kuldip,Kwan, Rainbow,Lin, Sophia,Lindgren, Andrea,Mezeyova, Janette,Sojo, Luis,Sun, Shaoyi,Xie, Zhiwei,Zenova, Alla Y.,de Boer, Gina
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- PHENYL METHANESULFONAMIDE DERIVATIVES USEFUL AS MGAT - 2 INHIBITORS
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The present invention provides compounds of Formula I or a pharmaceutical salt thereof, where the variables for R1, R2, and R3 are as described herein; methods of treating a condition such as hypertriglyceridemia; and processes for preparing the compounds.
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- Oximes and hydrazones that are useful in treating sexual dysfunction
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The present invention relates to oximes and hydrazones of formula (I) for the treatment of sexual dysfunction and to compositions containing compounds of formula (I) for the treatment of sexual dysfunction.
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Page/Page column 43
(2010/02/13)
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- Synthesis and structure-affinity relationships of 4-(5-Aryl-1,2,3,6-tetrahydropyridino)pyrimidine derivatives as corticotropin-releasing factor1 receptor antagonists
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Recently, various non-peptide corticotropin-releasing factor1 (CRF1) receptor antagonists have been reported. Structure-affinity relationships (SARs) of non-peptide CRF1 antagonists suggest that such antagonists can be constructed of three units: a hydrophobic unit (Up-Area), a proton accepting unit (Central-Area), and an aromatic unit (Down-Area). We previously presented 4-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives including potent CRF receptor ligands 1a and 1b and proposed that the 4-aryl-1,2,3,6-tetrahydropyridino moiety might be useful as a substituent in the Up-Area. Our interest shifted to 5-aryl-1,2,3,6-tetrahydropyridinopyrimidine derivatives 2, among which compound 2m (CRA0165) had highest affinity for CRF1 receptors (IC50=11 nM). We report here the design, synthesis and SARs of derivatives 2.
- Kumagai, Toshihito,Okubo, Taketoshi,Kataoka-Okubo, Hiromi,Chaki, Shigeyuki,Okuyama, Shigeru,Nakazato, Atsuro
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p. 1349 - 1355
(2007/10/03)
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