NNC 55-0396

NNC 55-0396 (NNC 55-0396 dihydrochloride) is a blood-brain-barrier-permeable T-type Ca²⁺ channel inhibitor and pan-P450 inhibitor. NNC 55-0396 selectively inhibits T-type Ca²⁺ channels, suppresses HIF-1α expression and stability and inhibits Kv currents. NNC 55-0396 reduces brain infarct and attenuates neurological dysfunction. NNC 55-0396 inhibits the activity of multiple P450 enzymes. NNC 55-0396 (free base) can be used for the research of brain injury, hypertension, and glioblastoma^{[1][2][3][4][5]}. In Vitro:NNC 55-0396 potently inhibits recombinant human CYP3A4 and CYP2D6 at 100 nM and 10 μM, with weaker or no inhibition of recombinant human CYP1A2, CYP2E1, CYP2C9, CYP2C19, and CYP2C8 at these concentrations^[2].
NNC 55-0396 inhibits recombinant human CYP3A4 BFC debenzylation activity with an IC₅₀ of 300 nM and a K_i of 210 nM^[2].
NNC 55-0396 inhibits recombinant human CYP2D6 AMMC N-demethylation activity with an IC₅₀ of 29 nM and a K_i of 2.8 nM^[2].
NNC 55-0396 inhibits CYP3A4-mediated testosterone 6β-hydroxylase activity in human liver microsomes with an IC₅₀ of 11.0 μM and a K_i of 3.9 μM^[2].
NNC 55-0396 inhibits CYP2D6-mediated harmaline metabolism in human liver microsomes with an IC₅₀ of 72.6 nM and a K_i of 57.1 nM^[2].
NNC 55-0396 (1-20 μM; 72 h) inhibits the growth of HepG2 cells more potently in galactose medium than glucose medium^[3].
NNC 55-0396 (1-5 μM; 5 h) dose-dependently inhibits hypoxia-induced HIF-1α protein stability in HepG2 cells, with a near-complete reduction at 5 μM after 4 h hypoxic incubation, without affecting HIF-1β levels^[3].
NNC 55-0396 (1-5 μM; 5 h) dose-dependently increases the hydroxylation of HIF-1α in HepG2 cells under hypoxic conditions, with a 6-fold increase observed at 5 μM after 4 h incubation^[3].
NNC 55-0396 (1-5 μM; 5 h) reduces hypoxia-induced mitochondrial ROS levels in HepG2 cells^[3].
NNC 55-0396 (1 μM) decreases the half-life of hypoxia-stabilized HIF-1α in HepG2 cells, reducing it from over 80 minutes to less than 70 minutes^[3].
NNC 55-0396 (1-5 μM; 5 h) inhibits Desferrioxamine-induced HIF-1α stabilization in HepG2 cells, with a 50% reduction observed at 5 μM after 4 h incubation^[3].
NNC 55-0396 (1-5 μM; 75 min) reduces hypoxia-induced HIF-1α protein levels in HepG2 cells, with significant suppression observed at 1 μM and 5 μM^[3].
NNC 55-0396 (1-5 μM; 75 min) inhibits hypoxia-induced phosphorylation of mTOR and p70S6K in HepG2 cells, with a 70% reduction in phospho-mTOR levels observed at 5 μM after 15 min hypoxic incubation^[3].
NNC 55-0396 (1-5 μM; 17 h) dose-dependently reduces hypoxia-induced VEGF expression in HepG2 cells, with significant suppression observed at 1 μM and 5 μM after 16 h hypoxic incubation^[3].
NNC 55-0396 (0.001-10 mM; 1 min) dose-dependently inhibits K_v currents in freshly isolated rabbit coronary arterial smooth muscle cells with an IC₅₀ of 0.08 mM^[4].
NNC 55-0396 potently blocks recombinant Cav3.1 T-type calcium channels in HEK293 cells with an IC₅₀ of 6.8 μM, via a state-dependent^[5]. In Vivo:NNC 55-0396 (5-20 mg/kg; i.p.; 2 doses) significantly reduces MCAO/R-induced ischemic brain injury and associated neurological dysfunctions^[1].
NNC 55-0396 (10-20 mg/kg; i.p.; every 2 days for 20 days) significantly reduces glioblastoma tumor weight by 40-60% and suppresses tumor angiogenesis via reduced HIF-1α, VEGF, and PECAM-1 expression in a subcutaneous mouse xenograft model^[3].