IC50: 9, 14 and 15 nM for rat, human and mouse erythrocyte KCa3.1 channels, respectively.
NS 6180 is a potent KCa3.1 channel blocker. KCa3.1 (the Ca2+-activated K+ channel, encoded by the KCNN4 gene) plays a key role in these processes by participating in the regulation of calcium entry.
In vitro: NS6180 blocked cloned human KCa3.1 channels via T250 and V275, while the same amino acid residues conferred sensitivity to triarylmethanes such as like TRAM-34. NS6180 blocked endogenously expressed KCa3.1 channels in human, mouse and rat erythrocytes with similar potencies. Rat and mouse splenocyte proliferation was suppressed NS6180 at submicrolar concentrations, which potently inhibited IL-2 and IFN-g production, exerting smaller effects on IL-4 and TNF-a and no effect on IL-17 production. After induction of colitis, antibody staining exhibited KCa3.1 channels in healthy colon and strong up-regulation in association with infiltrating immune cells [1].
In vivo: Despite poor plasma exposure, NS6180 (3 and 10 mg·kg-1 b.i.d.) abolished colon inflammation and improved body weight gain effectively, just as the standard IBD drug sulfasalazine (300 mg·kg-1 q.d.). The benzothiazinone NS6180 was potent on recombinant and endogenously expressed KCa3.1 channels, selectivity and molecular site of action. Furthermore, the effect of NS6180 characterize its pharmacokinetics on the activity of T-lymphocytes from wild-type and KCa3.1–/– knockout mice and show that it abolishes inflammation in an animal model of IBD [1].
Clinical trial: So far, no clinical study has been conducted.
Reference:
[1] Strbk D, Brown DT, Jenkins DP, Chen YJ, Coleman N, Ando Y, Chiu P, Jrgensen S, Demnitz J, Wulff H, Christophersen P. NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease. Br J Pharmacol. 2013 Jan;168(2):432-44.