Nepicastat (SYN-117) HCl

Catalog No.S2695

Nepicastat (SYN-117) HCl is a potent and selective inhibitor of both bovine and human dopamine-β-hydroxylase with IC50 of 8.5 nM and 9 nM, with negligible affinity for twelve other enzymes and thirteen neurotransmitter receptors. Phase 2.

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Nepicastat (SYN-117) HCl Chemical Structure

Nepicastat (SYN-117) HCl Chemical Structure
Molecular Weight: 331.81

Validation & Quality Control

Quality Control & MSDS

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Product Description

Biological Activity

Description Nepicastat (SYN-117) HCl is a potent and selective inhibitor of both bovine and human dopamine-β-hydroxylase with IC50 of 8.5 nM and 9 nM, with negligible affinity for twelve other enzymes and thirteen neurotransmitter receptors. Phase 2.
Targets Bovine dopamine-beta-hydroxylase [1] Human dopamine-beta-hydroxylase [1]
IC50 8.5 nM 9 nM
In vitro In vitro, Nepicastat hydrochloride shows the selective and concentration-dependent inhibition effects on bovine and human dopamine-beta-hydroxylase activity with IC50 of 8.5 nM and 9.0 nM, respectively. While Nepicastat hydrochloride has negligible affinity for twelve other enzymes and thirteen neurotransmitter receptors. [1]
In vivo In the artery, left ventricle and cerebral cortex of spontaneously hypertensive rats (SHRs), Nepicastat hydrochloride reduces noradrenaline content, and increases dopamine content and dopamine/noradrenaline ratio in a dose-dependent manner. In addition, Nepicastat hydrochloride also produces the similar effects on noradrenaline, dopamine and dopamine/noradrenaline ratio in tissues and plasma of beagle dogs. [1] In inactin-anesthetized SHRs, Nepicastat hydrochloride (3 mg/kg, i.v.) produces the antihypertensive effects and causes a significant decrease in renal vascular resistance (38%) and an increase in renal blood flow (22%). [2] In dogs with chronic heart failure, low-dose Nepicastat hydrochloride (0.5 mg/kg) prevents left ventricular (LV) dysfunction and remodeling, and combination therapy of Nepicastat hydrochloride and enalapril results in additional improvements in all morphological features. [3] In rat brain, Nepicastat hydrochloride at a dose of 50 mg/kg ( i.p.) leads to the reduction of norepinephrine (NE) and blocks cocaine-primed reinstatement of cocaine seeking. [4]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro studies Bovine and human dopamine-beta-hydroxylase activity are assayed by measuring the conversion of tyramine to octopamine. Human dopamine-beta-hydroxylase is purified from the culture medium of the neuroblastoma cell line SK-N-SH. The assay is performed at pH 5.2 and 32°C in a medium containing 0.125 M sodium acetate, 10 mM fumarate, 0.5 ± 2 μM CuSO4, 0.1 mg/mL catalase, 0.1 mM tyramine and 4 mM ascorbate. In a typical assay, 0.5 ± 1 mu of enzyme are added to the reaction mixture and, subsequently, a substrate mixture containing catalase, tyramine and ascorbate is added to initiate the reaction (final volume of 0.2 mL). Samples are incubated with or without the appropriate concentration of nepicastat (RS-25560-197, S-enantiomer) or RS-25560-198 (R-enantiomer) at 37 °C for 30-40 minutes. The reaction is quenched by the stop solution containing 25 mM EDTA and 240 μM 3-hydroxytyramine (internal standard). The samples are analysed for octopamine by reverse phase high pressure liquid chromatography (h.p.l.c.) with ultraviolet (u.v.)-detection at 280 nM. The h.p.l.c. run is carried out at a flow rate of 1 mL/min with a LiChroCART 125-4 RP-18 column and isocratic elution with 10 mM acetic acid, 10 mM 1-heptane sulphonic acid, 12 mM tetrabutyl ammonium phosphate and 10% methanol. The remaining % activity is calculated based on controls (without RS 25560), corrected with internal standards and fitted to a non-linear four-parameter concentration-response curve. The activity of nepicastat at twelve selected enzymes and receptors is determined by use of established assays. Binding data are analysed by iterative curve-fitting to a four parameter logistic equation. Ki values are calculated from IC50 values by the Cheng-Pruso€ equation. Enzyme inhibitory activity is expressed as IC50 (concentration required to produce 50% inhibition of enzyme activity).

Animal Study: [1]

Animal Models Spontaneously hypertensive rats (SHRs).
Formulation Nepicastat hydrochloride is dissolved in distilled water.
Dosages ≤100 mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Stanley WC, et al. Br J Pharmacol. 1997, 121(8), 1803-1809.

[2] Stanley WC, et al. J Cardiovasc Pharmacol. 1998, 31(6), 963-970.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01704196 Completed Cocaine Dependence National Institute on Drug Abuse (NIDA) April 2013 Phase 2
NCT00659230 Completed Posttraumatic Stress Disorder Tuscaloosa Research & Education Advancement Corporation|B  ...more Tuscaloosa Research & Education Advancement Corporation|Biotie Therapies Inc.|Ralph H. Johnson VA Medical Center|Baylor College of Medicine|VA Office of Research and Development|San Diego Veterans Healthcare System April 2009 Phase 2
NCT00656357 Completed Cocaine Dependence Biotie Therapies Inc.|National Institute on Drug Abuse (N  ...more Biotie Therapies Inc.|National Institute on Drug Abuse (NIDA) June 2008 Phase 1|Phase 2
NCT00641511 Completed Post Traumatic Stress Disorder (PTSD) Michael Debakey Veterans Affairs Medical Center|Lori Davi  ...more Michael Debakey Veterans Affairs Medical Center|Lori Davis, MD Tuscaloosa VA Medical Center|Ralph H. Johnson VA Medical Center|Biotie Therapies Inc. June 2008 Phase 2

Chemical Information

Download Nepicastat (SYN-117) HCl SDF
Molecular Weight (MW) 331.81
Formula

C14H15F2N3S.HCl

CAS No. 170151-24-3
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 66 mg/mL (198.9 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (S)-5-(aminomethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazole-2(3H)-thione hydrochloride

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