Design and synthesis of sulfonamidophenylethylureas as novel cardiac myosin activator

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>To optimize the lead urea scaffold <B>1</B> and <B>2</B> as selective cardiac myosin ATPase activator, a series of urea derivatives have been synthesized to explore its structure activity relationship. Among them <I>N,N</I>-dimethyl-4-(2-(3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (<B>13</B>, CMA = 91.6%, FS = 17.62%; EF = 11.55%), <I>N,N</I>-dimethyl-4-(2-(1-methyl-3-(3-phenylpropyl)ureido)ethyl)benzene sulfonamide (<B>40</B>, CMA = 52.3%, FS = 38.96%; EF = 24.19%) and <I>N,N</I>-dimethyl-4-(2-(3-methyl-3-(3-phenylpropyl)ureido)ethyl)benzenesulfonamide (<B>41</B>, CMA = 47.6%, FS = 23.19%; EF = 15.47%) proved to be efficient to activate the cardiac myosin <I>in vitro</I> and <I>in vivo</I>. Further the % change in ventricular cell contractility at 5 μM of <B>13</B> (47.9 ± 3.2), <B>40</B> (45.5 ± 2.4) and <B>41</B> (63.5 ± 2.2) showed positive inotropic effect in isolated rat ventricular myocytes. The potent compounds <B>13, 40, 41</B> were highly selective for cardiac myosin over skeletal and smooth muscle myosin, thus proving them these new urea derivatives is a novel scaffold for discovery of cardiac myosin activators for the treatment of systolic heart failure.</P> <P><B>Highlights</B></P> <P> <UL> <LI> SAR study of sulfonamidophenylethylureas discovered highly potent inotrope. </LI> <LI> These urea analogs are selective cardiac myosin ATPase activators. </LI> <LI> Compound <B>13</B>, <B>40</B>, <B>41</B> shows 17.6, 38.9, 23.2% fractional shortening in the echocardiographic study with rat. </LI> <LI> The cell contractility of <B>13</B>, <B>40</B>, <B>41</B> shows 47.9, 45.5, 63.5% at 5 µM in rat ventricle cells. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>