243137-99-7Relevant academic research and scientific papers
Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel
Yu, Zhiyi,Van Veldhoven, Jacobus P.D.,'T Hart, Ingrid M.E.,Kopf, Adrian H.,Heitman, Laura H.,Ijzerman, Adriaan P.
supporting information, p. 50 - 59 (2015/11/23)
We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [3H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.
Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and cns penetrable BACE inhibitors for the treatment of alzheimers disease
Huang, Hongbing,La, Daniel S.,Cheng, Alan C.,Whittington, Douglas A.,Patel, Vinod F.,Chen, Kui,Dineen, Thomas A.,Epstein, Oleg,Graceffa, Russell,Hickman, Dean,Kiang,Louie, Steven,Luo, Yi,Wahl, Robert C.,Wen, Paul H.,Wood, Stephen,Fremeau, Robert T.
, p. 9156 - 9169 (2013/01/15)
A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.
