NNC 55-0396 free base

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NNC 55-0396 free base is a blood-brain-barrier-permeable T-type Ca²⁺ channel inhibitor and pan-P450 inhibitor. NNC 55-0396 free base selectively inhibits T-type Ca²⁺ channels, suppresses HIF-1α expression and stability and inhibits Kv currents. NNC 55-0396 free base reduces brain infarct and attenuates neurological dysfunction. NNC 55-0396 free base inhibits the activity of multiple P450 enzymes. NNC 55-0396 (free base) can be used for the research of brain injury, hypertension, and glioblastoma.

For research use only. We do not sell to patients.

NNC 55-0396 free base Chemical Structure

CAS No. : 357400-14-7

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•Related Proteins:

View All Calcium Channel Isoform Specific Products:

View All Isoforms

N-type calcium channel L-type calcium channel P/Q-type calcium channel T-type calcium channel Calcium Channel

View All Cytochrome P450 Isoform Specific Products:

View All Isoforms

CYP1 CYP2 CYP3 CYP4 CYP11 CYP17 Aromatase/CYP19A1 CYP26 CYP51 CYP1A2 CYP2D6 CYP2C9 CYP2C19 CYP3A CYP3A4 CYP17A1

Biological Activity
Purity & Documentation
References
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Description

IC₅₀ & Target^[3]^[2]

L-type calcium channel

CYP3A4

300 nM (IC₅₀)

CYP3A4

210 nM (Ki)

CYP2D6

29 nM (IC₅₀)

CYP2D6

2.8 nM (Ki)

In Vitro

NNC 55-0396 free base 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 free base inhibits recombinant human CYP3A4 BFC debenzylation activity with an IC₅₀ of 300 nM and a K_i of 210 nM^[2].
NNC 55-0396 free base 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 free base 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 free base 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) free base inhibits the growth of HepG2 cells more potently in galactose medium than glucose medium^[3].
NNC 55-0396 (1-5 μM; 5 h) free base 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) free base 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) free base reduces hypoxia-induced mitochondrial ROS levels in HepG2 cells^[3].
NNC 55-0396 (1 μM) free base 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) free base 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) free base 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) free base 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) free base 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) free base 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 free base potently blocks recombinant Cav3.1 T-type calcium channels in HEK293 cells with an IC₅₀ of 6.8 μM, via a state-dependent^[5].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Viability Assay^[3]

Cell Line:	human liver carcinoma HepG2 cells
Concentration:	1 μM; 2 μM; 5 μM; 7 μM; 10 μM; 20 μM
Incubation Time:	72 h
Result:	Exhibited stronger inhibitory effects on cell growth in galactose medium than in glucose medium. Increased glucose/galactose cell growth ratios significantly at concentrations of 5, 7, 10, and 20 μM.

Western Blot Analysis^[3]

Cell Line:	human liver carcinoma HepG2 cells
Concentration:	1 μM; 5 μM
Incubation Time:	5 h
Result:	Suppressed hypoxia-induced HIF-1α protein stability in a dose-dependent manner, with no effect on HIF-1β stability. Reduced HIF-1α expression to ~80% of hypoxic control levels at 1 μM. Reduced HIF-1α expression to ~20% of hypoxic control levels at 5 μM (p<0.001).\nIncreased the ratio of hydroxy-HIF-1α to total HIF-1α in a dose-dependent manner. Increased the ratio to ~250% of control levels at 1 μM. Increased the ratio to ~600% of control levels at 5 μM (p<0.001).

Western Blot Analysis^[3]

Cell Line:	human liver carcinoma HepG2 cells
Concentration:	1 μM; 5 μM
Incubation Time:	5 h
Result:	Inhibited DFO-induced HIF-1α stabilization. Reduced HIF-1α expression to ~100% of DFO-treated control levels at 1 μM. Reduced HIF-1α expression to ~50% of DFO-treated control levels at 5 μM (p<0.01).

Western Blot Analysis^[3]

Cell Line:	human liver carcinoma HepG2 cells
Concentration:	1 μM; 5 μM
Incubation Time:	75 min
Result:	Repressed hypoxia-induced phosphorylation of mTOR and p70S6K. Reduced phospho-mTOR levels to 0.8-fold of hypoxic control levels at 1 μM. Reduced phospho-mTOR levels to 0.3-fold of hypoxic control levels at 5 μM. Reduced phospho-p70S6K levels to 0.9-fold and 0.8-fold of hypoxic control levels at 1 μM and 5 μM, respectively.

ELISA Assay^[3]

Cell Line:	human liver carcinoma HepG2 cells
Concentration:	1 μM; 5 μM
Incubation Time:	17 h
Result:	Decreased hypoxia-induced VEGF expression in a dose-dependent manner. Reduced relative VEGF expression to ~220% of normoxic control levels at 1 μM (vs ~280% for hypoxic control; p<0.01). Reduced relative VEGF expression to ~180% of normoxic control levels at 5 μM (p<0.01).

In Vivo

NNC 55-0396 free base (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) free base 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].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:	ddY mice (male, 3 weeks old, acclimated for a few weeks before experiments)^[1]
Dosage:	5 mg/kg; 20 mg/kg
Administration:	i.p.; 2 doses
Result:	Reduced MCAO/R-induced infarct area (at all measured distances from bregma) and infarct volume to ~30 mm³ (5 mg/kg i.p. pre-occlusion) and ~45 mm³ vs. vehicle ~70 mm³. Tended to attenuate some neurological dysfunctions, including increased test latency in the passive avoidance test and reduced time spent in right-biased bending.

Animal Model:	BALB/c-nu/nu (athymic nude) (4-week-old female, subcutaneous glioblastoma xenograft model)^[3]
Dosage:	10 mg/kg; 20 mg/kg
Administration:	i.p.; every 2 days for 20 days
Result:	Reduced xenograft tumor volume and weight relative to vehicle controls. Significantly reduced tumor weight (p<0.01 for 10 mg/kg, p<0.001 for 20 mg/kg). Significantly reduced HIF-1α, VEGF, and PECAM-1 expression levels in tumor tissue. Significantly decreased microvessel density (p<0.001 for 10 mg/kg, p<0.01 for 20 mg/kg). Caused no weight loss or liver toxicity in treated mice.

Molecular Weight

491.64

Formula

C₃₀H₃₈FN₃O₂

CAS No.

357400-14-7

SMILES

O=C(C1CC1)O[C@]2([C@H](C3=CC=C(F)C=C3CC2)C(C)C)CCN(C)CCCC4=NC5=CC=CC=C5N4

Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Purity & Documentation

Handling Instructions (2659 KB)

References

[1]. Matsuda S, et al. NNC 55-0396, a T-type calcium channel blocker, protects against the brain injury induced by middle cerebral artery occlusion and reperfusion in mice. J Pharmacol Sci. 2019;140(2):193-196.

[2]. Bui PH, et al. The mibefradil derivative NNC55-0396, a specific T-type calcium channel antagonist, exhibits less CYP3A4 inhibition than mibefradil. Drug Metab Dispos. 2008;36(7):1291-1299.

[3]. Kim KH, et al. NNC 55-0396, a T-type Ca2+ channel inhibitor, inhibits angiogenesis via suppression of hypoxia-inducible factor-1α signal transduction. J Mol Med (Berl). 2015;93(5):499-509.

[4]. Son YK, et al. Ca2+ channel inhibitor NNC 55-0396 inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. J Pharmacol Sci. 2014;125(3):312-319.

[5]. Li M, et al. Towards selective antagonists of T-type calcium channels: design, characterization and potential applications of NNC 55-0396. Cardiovasc Drug Rev. 2005;23(2):173-196. [Content Brief]