Safety of 2-BromobenzonitrileIn 2022 ,《VU6036720: the first potent and selective in vitro inhibitor of heteromeric Kir4.1/5.1 inward rectifier potassium channels》 appeared in Molecular Pharmacology. The author of the article were McClenahan, Samantha J.; Kent, Caitlin N.; Kharade, Sujay V.; Isaeva, Elena; Williams, Jade C.; Han, Changho; Terker, Andrew; Gresham, Robert III; Lazarenko, Roman M.; Days, Emily L.; Romaine, Ian M.; Bauer, Joshua A.; Boutaud, Olivier; Sulikowski, Gary A.; Harris, Raymond; Weaver, C. David; Staruschenko, Alexander; Lindsley, Craig W.; Denton, Jerod S.. The article conveys some information:
Heteromeric Kir4.1/Kir5.1 (KCNJ10/KCNJ16) inward rectifier potassium (Kir) channels play key roles in the brain and kidney, but pharmacol. tools for probing their physiol. and therapeutic potential have not been developed. Here, we report the discovery, in a high-throughput screening of 80,475 compounds, of the moderately potent and selective inhibitor VU0493690, which we selected for characterization and chem. optimization. VU0493690 concentration-dependently inhibits Kir4.1/5.1 with an IC50 of 0.96 μM and exhibits at least 10-fold selectivity over Kir4.1 and ten other Kir channels. Multidimensional chem. optimization of VU0493690 led to the development of VU6036720, the most potent (IC50 = 0.24 μM) and selective (>40-fold over Kir4.1) Kir4.1/5.1 inhibitor reported to date. Cell-attached patch single-channel recordings revealed that VU6036720 inhibits Kir4.1/5.1 activity through a reduction of channel open-state probability and single-channel current amplitude. Elevating extracellular potassium ion by 20 mM shifted the IC50 6.8-fold, suggesting that VU6036720 is a pore blocker that binds in the ion-conduction pathway. Mutation of the “”rectification controller”” asparagine 161 to glutamate (N161E), which is equivalent to small-mol. binding sites in other Kir channels, led to a strong reduction of inhibition by VU6036720. Renal clearance studies in mice failed to show a diuretic response that would be consistent with inhibition of Kir4.1/5.1 in the renal tubule. Drug metabolism and pharmacokinetics profiling revealed that high VU6036720 clearance and plasma protein binding may prevent target engagement in vivo. In conclusion, VU6036720 represents the current state-of-the-art Kir4.1/5.1 inhibitor that should be useful for probing the functions of Kir4.1/5.1 in vitro and ex vivo. In the part of experimental materials, we found many familiar compounds, such as 2-Bromobenzonitrile(cas: 2042-37-7Safety of 2-Bromobenzonitrile)
2-Bromobenzonitrile(cas: 2042-37-7) belongs to a group of ortho-substituted bromobenzenes that have varying hepatotoxicity effects in the presence of rat liver microsomes in vitro. 2-Bromobenzonitrile is also used as a starting material to synthesize novel benzothiophene derivatives that were found to exhibit antibacterial and antifungal activity.Safety of 2-Bromobenzonitrile
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts