Nepicastat hydrochloride | SYN117 | RS-25560-197 | CAS#170151-24-3 | 173997-05-2

MedKoo Cat#: 510304 | Name: Nepicastat HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Nepicastat, also known as SYN117 and RS-25560-197, is an inhibitor of dopamine beta-hydroxylase, an enzyme that catalyzes the conversion of dopamine to norepinephrine. It has been studied as a possible treatment for congestive heart failure, and appears to be well tolerated. As of 2012, clinical trials to assess nepicastat as a treatment for post-traumatic stress disorder (PTSD) and cocaine dependence have been completed. In Phase 2 study treatment with nepicastat was not effective in relieving PTSD-associated symptoms when compared to placebo.

Chemical Structure

Nepicastat HCl

CAS#170151-24-3 (HCl)

Theoretical Analysis

MedKoo Cat#: 510304

Name: Nepicastat HCl

CAS#: 170151-24-3 (HCl)

Chemical Formula: C14H15F2N3S

Exact Mass: 0.0000

Molecular Weight: 295.35

Elemental Analysis: C, 56.93; H, 5.12; F, 12.86; N, 14.23; S, 10.86

Price and Availability

Size	Price	Availability
25mg	USD 150.00	Ready to ship
50mg	USD 250.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 850.00	Ready to ship
500mg	USD 1,850.00	Ready to ship
1g	USD 3,150.00	Ready to ship
2g	USD 5,650.00	Ready to ship

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Related CAS #

170151-24-3 (HCl) 173997-05-2 (free base) 195881-94-8 (HCl R isomer) 177645-08-8 (HCl hydrate)

Synonym

SYN117; SYN-117; SYN 117; RS25560197; RS25560-197; RS-25560-197; RS 25560-197; Nepicastat; Nepicastat HCl

IUPAC/Chemical Name

(S)-5-(aminomethyl)-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1H-imidazole-2(3H)-thione hydrochloride

InChi Key

DIPDUAJWNBEVOY-PPHPATTJSA-N

InChi Code

InChI=1S/C14H15F2N3S.ClH/c15-9-3-8-4-10(1-2-12(8)13(16)5-9)19-11(6-17)7-18-14(19)20;/h3,5,7,10H,1-2,4,6,17H2,(H,18,20);1H/t10-;/m0./s1

SMILES Code

S=C1NC=C(CN)N1[C@@H]2CC3=C(C(F)=CC(F)=C3)CC2.[H]Cl

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Related CAS# 170151-24-3 ( Nepicastat HCl); 173997-05-2 ( Nepicastat free base).

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#BBC70417

QC Data

View QC data: current batch, Lot#BBC70417

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

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.

In vitro activity:

Under the optimized conditions, nepicastat inhibited SK-N-SH DBH enzyme (Fig. 4) with IC50 values of 40 (36; 44) nM. The inhibition produced by 300 nM nepicastat was fully reversed by a two-step centrifugation and dilution procedure (data not shown). The modality of DBH inhibition by nepicastat was evaluated in relation to two of the enzyme substrates, tyramine and ascorbic acid. The velocities determined at increasing concentrations of tyramine in the presence of 10, 30 and 100 nM of nepicastat are shown in Fig. 6A and the ones determined at increasing concentrations of ascorbic acid in the presence of 10 and 30 nM nepicastat are represented in Fig. 6B. Non-linear regression analysis was performed as above. The kinetic parameters Ki and constant α derived from these curves are shown in Table 1. Concerning the substrate ascorbic acid, nepicastat inhibits DBH with a Ki value of 0.1 (0.0; 0.5) µM. Reference: Eur J Pharmacol. 2015 Mar 15;751:50-8. https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(15)00067-9

In vivo activity:

Nepicastat (30 mg/kg, p.o.) reduced DβH activity by 93% and 80% in the adrenals at 4 h and 8 h postdrug administration, accompanied by significant reductions in NE and epinephrine tissue levels and an increase in DA levels and of DA/NE tissue ratios, with similar findings for NE, DA and of DA/NE tissue ratios in left ventricle and kidney. DβH activity in the left ventricle and kidney showed a high degree of variability, which does not allow corroboration of the effects of nepicastat upon catecholamine tissue levels. Reference: Clin Exp Hypertens. 2020;42(2):118-125. https://www.tandfonline.com/doi/full/10.1080/10641963.2019.1583245

	Solvent	mg/mL	mM
Solubility
	DMSO	6.0	20.30

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 295.35 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. Bicker J, Alves G, Fortuna A, Soares-da-Silva P, Falcão A. In vitro assessment of the interactions of dopamine β-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein. Eur J Pharm Sci. 2018 May 30;117:35-40. doi: 10.1016/j.ejps.2018.02.006. Epub 2018 Feb 8. PMID: 29428540. 2. Bonifácio MJ, Sousa F, Neves M, Palma N, Igreja B, Pires NM, Wright LC, Soares-da-Silva P. Characterization of the interaction of the novel antihypertensive etamicastat with human dopamine-β-hydroxylase: comparison with nepicastat. Eur J Pharmacol. 2015 Mar 15;751:50-8. doi: 10.1016/j.ejphar.2015.01.034. Epub 2015 Jan 29. PMID: 25641750.

In vivo protocol:

1. Catelas DN, Serrão MP, Soares-Da-Silva P. Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland. Clin Exp Hypertens. 2020;42(2):118-125. doi: 10.1080/10641963.2019.1583245. Epub 2019 Mar 1. PMID: 30821508. 2. Stanley WC, Lee K, Johnson LG, Whiting RL, Eglen RM, Hegde SS. Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor. J Cardiovasc Pharmacol. 1998 Jun;31(6):963-70. doi: 10.1097/00005344-199806000-00023. PMID: 9641484.

1: Devoto P, Fattore L, Antinori S, Saba P, Frau R, Fratta W, Gessa GL. Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation. Addict Biol. 2014 Aug 19. doi: 10.1111/adb.12178. [Epub ahead of print] PubMed PMID: 25135633. 2: Cooper DA, Kimmel HL, Manvich DF, Schmidt KT, Weinshenker D, Howell LL. Effects of pharmacologic dopamine β-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther. 2014 Jul;350(1):144-52. doi: 10.1124/jpet.113.212357. Epub 2014 May 9. PubMed PMID: 24817036; PubMed Central PMCID: PMC4056266. 3: Manvich DF, DePoy LM, Weinshenker D. Dopamine β-hydroxylase inhibitors enhance the discriminative stimulus effects of cocaine in rats. J Pharmacol Exp Ther. 2013 Dec;347(3):564-73. doi: 10.1124/jpet.113.207746. Epub 2013 Sep 25. PubMed PMID: 24068832; PubMed Central PMCID: PMC3836309. 4: Zaru A, Maccioni P, Colombo G, Gessa GL. The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats. Br J Nutr. 2013 Oct;110(8):1524-33. doi: 10.1017/S0007114513000743. Epub 2013 Apr 8. PubMed PMID: 23561307. 5: Schroeder JP, Epps SA, Grice TW, Weinshenker D. The selective dopamine β-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior. Neuropsychopharmacology. 2013 May;38(6):1032-8. doi: 10.1038/npp.2012.267. Epub 2013 Jan 3. PubMed PMID: 23303068; PubMed Central PMCID: PMC3629392. 6: Devoto P, Flore G, Saba P, Bini V, Gessa GL. The dopamine beta-hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant-induced dopamine release in the prefrontal cortex. Addict Biol. 2014 Jul;19(4):612-22. doi: 10.1111/adb.12026. Epub 2013 Jan 7. PubMed PMID: 23289939. 7: Gaval-Cruz M, Liles LC, Iuvone PM, Weinshenker D. Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice. PLoS One. 2012;7(11):e50583. doi: 10.1371/journal.pone.0050583. Epub 2012 Nov 27. PubMed PMID: 23209785; PubMed Central PMCID: PMC3507785. 8: Kapoor A, Shandilya M, Kundu S. Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms. PLoS One. 2011;6(10):e26509. doi: 10.1371/journal.pone.0026509. Epub 2011 Oct 20. PubMed PMID: 22028891; PubMed Central PMCID: PMC3197665. 9: Schroeder JP, Cooper DA, Schank JR, Lyle MA, Gaval-Cruz M, Ogbonmwan YE, Pozdeyev N, Freeman KG, Iuvone PM, Edwards GL, Holmes PV, Weinshenker D. Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine β-hydroxylase. Neuropsychopharmacology. 2010 Nov;35(12):2440-9. doi: 10.1038/npp.2010.127. Epub 2010 Aug 25. PubMed PMID: 20736996; PubMed Central PMCID: PMC2956132. 10: Gaval-Cruz M, Schroeder JP, Liles LC, Javors MA, Weinshenker D. Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures. Pharmacol Biochem Behav. 2008 Jun;89(4):556-62. doi: 10.1016/j.pbb.2008.02.009. Epub 2008 Feb 12. PubMed PMID: 18329701; PubMed Central PMCID: PMC2386143.