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ML252 hydrochloride is a selective inhibitor of KCNQ2 (Kv7.2) channel with IC50s of 69 nM, 2.92 μM, 0.12 μM and 0.20 μM for KCNQ2, KCNQ1 (Kv7.1), KCNQ2/Q3 and KCNQ4, respectively. ML252 hydrochloride also inhibits Cytochrome P450 with IC50s of 6.1 nM (CYP1A2), 18.9 nM (CYP2C9), 3.9 nM (CYP3A4), 19.9 nM (CYP2D6), respectively. ML252 hydrochloride shows highly brain penetrant[1][2]. | [in vivo]
ML252 (10 mg/kg, 3 mg/mL; ip; single dose; measured at 1 hr after) hydrochloride shows a highly brain penetrant with a B:P ratio of 1.9 and absolute brain levels of 672 nM in rat model[1].
ML252 hydrochloride has the metabolic stability unsuitable for oral administration[2].
| [IC 50]
KCNQ2: 69 nM (IC50); KCNQ1: 2.92 μM (IC50); KCNQ2/Q3: 0.12 μM (IC50); KCNQ4: 0.20 μM (IC50); CYP1A2: 6.1 μM (IC50); CYP2C9: 18.9 μM (IC50); CYP3A4: 3.9 μM (IC50); CYP2D6: 19.9 μM (IC50) | [References]
[1] Yu H, et al. Identification of a novel, small molecule inhibitor of KCNQ2 channels. 2011 Oct 28 [updated 2013 Feb 25]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010–. PMID:23658963
[2] Cheung YY, et al. Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor. J Med Chem. 2012 Aug 9;55(15):6975-9. DOI:10.1021/jm300700v |
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