Design and synthesis of sulfonamidophenylethylamides as novel cardiac myosin activator

• Published in: Bioorganic & medicinal chemistry 2019-09, Vol.27 (18), p.4110-4123
• Main Authors: Manickam, Manoj, Pillaiyar, Thanigaimalai, Namasivayam, Vigneshwaran, Boggu, Pulla Reddy, Sharma, Niti, Jalani, Hitesh B., Venkateswararao, Eeda, Lee, You-Jung, Jeon, Eun-Seok, Son, Min-Jeong, Woo, Sun-Hee, Jung, Sang-Hun
• Format: Article
• Language: English
• Subjects: Amide; Cardiac myosin activator; Inotrope; Structure-activity relationship; Systolic heart failure
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.07.041

[Display omitted] •N-Phenethyl-5-phenylpentanamides were explored as novel cardiac myosin activators.•Selective cardiac myosin ATPase activation of 13 and 27 are 48.5% and 55.0% at 10 µM.•The hemodynamic profiles of 13 and 27 in rat were greatly improved.•Potent compounds showed positive inotropic effect in isolated rat ventricular myocytes.•N,N-dimethylsulfonamide of 13 and 27 well fit into binding pocket of the enzyme. The sulfonamidophenylethylamide analogues were explored for finding novel and potent cardiac myosin activators. Among them, N-(4-(N,N-dimethylsulfamoyl)phenethyl-N-methyl-5-phenylpentanamide (13, CMA at 10 µM = 48.5%; FS = 26.21%; EF = 15.28%) and its isomer, 4-(4-(N,N-dimethylsulfamoyl)phenyl-N-methyl-N-(3-phenylpropyl)butanamide (27, CMA at 10 µM = 55.0%; FS = 24.69%; EF = 14.08%) proved to be efficient cardiac myosin activators both in in vitro and in vivo studies. Compounds 13 (88.2 + 3.1% at 5 µM) and 27 (46.5 + 2.8% at 5 µM) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds 13 and 27 were highly selective for cardiac myosin over skeletal and smooth muscle myosin, and therefore these potent and selective amide derivatives could be considered a new class of cardiac myosin activators for the treatment of systolic heart failure.