Targeting the Kv11.1 (hERG) channel with allosteric modulators. Synthesis and biological evaluation of three novel series of LUF7346 derivatives was written by van Veldhoven, Jacobus P. D.;Campostrini, Giulia;van Gessel, Constantijn J. E.;Ward-van Oostwaard, Dorien;Liu, Rongfang;Mummery, Christine L.;Bellin, Milena;IJzerman, Adriaan P.. And the article was included in European Journal of Medicinal Chemistry in 2021.COA of Formula: C8H8N2O This article mentions the following:
Three novel series of substituted benzophenones for their allosteric modulation of the human Kv11.1 (hERG) channel were synthesized and evaluated. Effects of this is compared with reference compound LUF7346 previously shown to shorten the action potential of cardiomyocytes derived from human stem cells. Most compounds behaved as neg. allosteric modulators (NAMs) of [3H]dofetilide binding to the channel. Compound III [R = 2-Cl; R1 = CH2cPr; X= Y = C] was the most potent amongst all ligands, remarkably reducing the affinity of dofetilide in competitive displacement assays. One of the other II [R = H; X = N] tested in a second radioligand binding set-up, displayed unusual displacement characteristics with a pseudo-Hill coefficient significantly distinct from unity, further indicative of its allosteric effects on the channel. Some compounds were evaluated in a more physiol. relevant context in beating cardiomyocytes derived from human induced pluripotent stem cells. Surprisingly, the compounds tested showed effects quite different from the reference NAM LUF7346. For instance, compound I [R = 3-Me] prolonged, rather than shortened, the field potential duration, while it did not influence this parameter when the field potential was already prolonged by dofetilide. In subsequent patch clamp studies on HEK293 cells expressing the hERG channel the compounds behaved as channel blockers. In conclusion, new allosteric modulators of the hERG channel were successfully synthesized and identified . Unexpectedly, their effects differed from the reference compound in functional assays on hERG-HEK293 cells and human cardiomyocytes, to the extent that the compounds behaved as stand-alone channel blockers. In the experiment, the researchers used many compounds, for example, 3-Amino-4-methoxybenzonitrile (cas: 60979-25-1COA of Formula: C8H8N2O).
3-Amino-4-methoxybenzonitrile (cas: 60979-25-1) belongs to nitriles. Trimerization of aromatic nitriles requires harsh reaction conditions, high temperatures, long reaction times, and pressure. Alkyl nitriles are sufficiently acidic to undergo deprotonation of the C-H bond adjacent to the CN group.Strong bases are required, such as lithium diisopropylamide and butyl lithium. The product is referred to as a nitrile anion. COA of Formula: C8H8N2O
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts