Omigapil maleate
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MedKoo CAT#: 525782

CAS#: 200189-97-5 (maleate)

Description: Omigapil maleate is a drug that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). The development for PD and ALS have been terminated due to lack of benefit, but Santhera Pharmaceuticals bought the compound for development for the treatment of congenital muscular dystrophy (CMD).


Chemical Structure

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Omigapil maleate
CAS# 200189-97-5 (maleate)

Theoretical Analysis

MedKoo Cat#: 525782
Name: Omigapil maleate
CAS#: 200189-97-5 (maleate)
Chemical Formula: C23H21NO5
Exact Mass: 0.00
Molecular Weight: 391.417
Elemental Analysis: C, 70.58; H, 5.41; N, 3.58; O, 20.44

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10mg USD 265
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Related CAS #: 181296-84-4 (free base)   200189-97-5 (maleate)    

Synonym: CGP 3466B; CGP-3466B; CGP3466B; TCH-346; TCH 346; TCH346; Omigapil maleate

IUPAC/Chemical Name: N-(dibenzo[b,f]oxepin-10-ylmethyl)-N-methylprop-2-yn-1-amine maleate

InChi Key: SQAZQLMBEHYFJA-BTJKTKAUSA-N

InChi Code: InChI=1S/C19H17NO.C4H4O4/c1-3-12-20(2)14-16-13-15-8-4-6-10-18(15)21-19-11-7-5-9-17(16)19;5-3(6)1-2-4(7)8/h1,4-11,13H,12,14H2,2H3;1-2H,(H,5,6)(H,7,8)/b;2-1-

SMILES Code: C#CCN(CC1=CC2=CC=CC=C2OC3=CC=CC=C13)C.O=C(O)/C=C\C(O)=O

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

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:

Product Data:
Biological target: Omigapil maleate is an orally bioavailable GAPDH nitrosylation inhibitor.
In vitro activity: CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10(-7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Reference: Naunyn Schmiedebergs Arch Pharmacol. 2000 Dec;362(6):526-37. https://pubmed.ncbi.nlm.nih.gov/11138845/
In vivo activity: This study demonstrates that the multifunctional protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is robustly nitrosylated in the CNS in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. GAPDH nitrosylation is blocked in vivo with daily administration of CGP3466b, a CNS-penetrant compound with an established safety profile in humans. Consistent with the known role of nitrosylated GAPDH (SNO-GAPDH) in neuronal cell death, blockade of SNO-GAPDH with CGP3466b attenuates neurologic disability and reduces axonal injury in EAE independent of effects on the immune system. Reference: Front Neurol. 2023 Jan 24;13:979659. https://pubmed.ncbi.nlm.nih.gov/36761918/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMF 20.0 51.10
DMSO 36.4 92.94
Ethanol 0.5 1.28
PBS (pH 7.2) 0.5 1.28
Water 3.9 10.00

Preparing Stock Solutions

The following data is based on the product molecular weight 391.42 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.

Recalculate based on batch purity %
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: 1. Wägner AM, Cloos P, Bergholdt R, Boissy P, Andersen TL, Henriksen DB, Christiansen C, Christgau S, Pociot F, Nerup J. Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase? Diabetologia. 2007 Mar;50(3):676-81. doi: 10.1007/s00125-006-0556-1. Epub 2007 Jan 10. PMID: 17216280. 2. Waldmeier PC, Spooren WP, Hengerer B. CGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease. Naunyn Schmiedebergs Arch Pharmacol. 2000 Dec;362(6):526-37. doi: 10.1007/s002100000300. PMID: 11138845. 3. Godfrey WH, Hwang S, Cho K, Shanmukha S, Gharibani P, Abramson E, Kornberg MD. Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis. Front Neurol. 2023 Jan 24;13:979659. doi: 10.3389/fneur.2022.979659. PMID: 36761918; PMCID: PMC9902867. 4. Liang F, Shi L, Zheng J, Chen S, Wang Y, Zhang J. Neuroprotective Effects of CGP3466B on Apoptosis Are Modulated by Protein-L-isoaspartate (D-aspartate) O-methyltransferase/Mst1 Pathways after Traumatic Brain Injury in Rats. Sci Rep. 2017 Aug 23;7(1):9201. doi: 10.1038/s41598-017-08196-3. PMID: 28835703; PMCID: PMC5569064.
In vitro protocol: 1. Wägner AM, Cloos P, Bergholdt R, Boissy P, Andersen TL, Henriksen DB, Christiansen C, Christgau S, Pociot F, Nerup J. Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase? Diabetologia. 2007 Mar;50(3):676-81. doi: 10.1007/s00125-006-0556-1. Epub 2007 Jan 10. PMID: 17216280. 2. Waldmeier PC, Spooren WP, Hengerer B. CGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease. Naunyn Schmiedebergs Arch Pharmacol. 2000 Dec;362(6):526-37. doi: 10.1007/s002100000300. PMID: 11138845.
In vivo protocol: 1. Godfrey WH, Hwang S, Cho K, Shanmukha S, Gharibani P, Abramson E, Kornberg MD. Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis. Front Neurol. 2023 Jan 24;13:979659. doi: 10.3389/fneur.2022.979659. PMID: 36761918; PMCID: PMC9902867. 2. Liang F, Shi L, Zheng J, Chen S, Wang Y, Zhang J. Neuroprotective Effects of CGP3466B on Apoptosis Are Modulated by Protein-L-isoaspartate (D-aspartate) O-methyltransferase/Mst1 Pathways after Traumatic Brain Injury in Rats. Sci Rep. 2017 Aug 23;7(1):9201. doi: 10.1038/s41598-017-08196-3. PMID: 28835703; PMCID: PMC5569064.

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1: Yu Q, Sali A, Van der Meulen J, Creeden BK, Gordish-Dressman H, Rutkowski A, Rayavarapu S, Uaesoontrachoon K, Huynh T, Nagaraju K, Spurney CF. Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy. PLoS One. 2013 Jun 6;8(6):e65468. doi: 10.1371/journal.pone.0065468. Print 2013. PubMed PMID: 23762378; PubMed Central PMCID: PMC3675144.

2: Erb M, Meinen S, Barzaghi P, Sumanovski LT, Courdier-Früh I, Rüegg MA, Meier T. Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency. J Pharmacol Exp Ther. 2009 Dec;331(3):787-95. doi: 10.1124/jpet.109.160754. Epub 2009 Sep 16. PubMed PMID: 19759319.

3: Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Rüegg MA. Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice. EMBO Mol Med. 2011 Aug;3(8):465-79. doi: 10.1002/emmm.201100151. Epub 2011 Jun 15. PubMed PMID: 21674808; PubMed Central PMCID: PMC3377088.

4: Harraz MM, Snyder SH. Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine. CNS Neurol Disord Drug Targets. 2015;14(6):757-63. Review. PubMed PMID: 26022259; PubMed Central PMCID: PMC4831565.

5: Snider NT, Portney DA, Willcockson HH, Maitra D, Martin HC, Greenson JK, Omary MB. Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346-Insensitive Nuclear Translocation of GAPDH. PLoS One. 2016 Aug 11;11(8):e0160982. doi: 10.1371/journal.pone.0160982. eCollection 2016. PubMed PMID: 27513663; PubMed Central PMCID: PMC4981434.

6: Yacoubian TA, Standaert DG. Targets for neuroprotection in Parkinson's disease. Biochim Biophys Acta. 2009 Jul;1792(7):676-87. doi: 10.1016/j.bbadis.2008.09.009. Epub 2008 Oct 1. Review. PubMed PMID: 18930814; PubMed Central PMCID: PMC2740981.

7: Miller R, Bradley W, Cudkowicz M, Hubble J, Meininger V, Mitsumoto H, Moore D, Pohlmann H, Sauer D, Silani V, Strong M, Swash M, Vernotica E; TCH346 Study Group. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology. 2007 Aug 21;69(8):776-84. PubMed PMID: 17709710.

8: Leigh PN, Swash M, Iwasaki Y, Ludolph A, Meininger V, Miller RG, Mitsumoto H, Shaw P, Tashiro K, Van Den Berg L. Amyotrophic lateral sclerosis: a consensus viewpoint on designing and implementing a clinical trial. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Jun;5(2):84-98. Review. PubMed PMID: 15204010.

9: LeWitt PA. Clinical trials of neuroprotection for Parkinson's disease. Neurology. 2004 Oct 12;63(7 Suppl 2):S23-31. Review. PubMed PMID: 15477583.

10: Jenner P. Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson's disease. Neurology. 2004 Oct 12;63(7 Suppl 2):S13-22. Review. PubMed PMID: 15477581.

11: Andringa G, Cools AR. The neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson's disease, the bilaterally MPTP-treated rhesus monkey. J Neural Transm Suppl. 2000;(60):215-25. PubMed PMID: 11205142.

12: Hara H, Uchimura T, Akashi N, Naganuma T, Aizawa T, Nagae Y, Masuda N. Simultaneous analytical method for the determination of TCH346 and its four metabolites in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2004;18(4):377-84. PubMed PMID: 14966843.

13: Jenkins JL, Tanner JJ. High-resolution structure of human D-glyceraldehyde-3-phosphate dehydrogenase. Acta Crystallogr D Biol Crystallogr. 2006 Mar;62(Pt 3):290-301. Epub 2006 Feb 22. PubMed PMID: 16510976.

14: Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, Dawson TM, Sawa A, Snyder SH. Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3887-9. Epub 2006 Feb 27. PubMed PMID: 16505364; PubMed Central PMCID: PMC1450161.

15: Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler P, Muller D, van Oostrum J, Waldmeier P, Furst P. Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl. J Biol Chem. 1998 Mar 6;273(10):5821-8. PubMed PMID: 9488718.

16: Matarredona ER, Meyer M, Seiler RW, Widmer HR. CGP 3466 increases survival of cultured fetal dopaminergic neurons. Restor Neurol Neurosci. 2003;21(1-2):29-37. PubMed PMID: 12808200.

17: Groeneveld GJ, van Muiswinkel FL, de Leeuw van Weenen J, Blauw H, Veldink JH, Wokke JH, van den Berg LH, Bär PR. CGP 3466B has no effect on disease course of (G93A) mSOD1 transgenic mice. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Dec;5(4):220-5. PubMed PMID: 15799550.

18: Huebscher KJ, Lee J, Rovelli G, Ludin B, Matus A, Stauffer D, Fürst P. Protein isoaspartyl methyltransferase protects from Bax-induced apoptosis. Gene. 1999 Nov 29;240(2):333-41. PubMed PMID: 10580153.

19: Carlile GW, Chalmers-Redman RM, Tatton NA, Pong A, Borden KE, Tatton WG. Reduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer. Mol Pharmacol. 2000 Jan;57(1):2-12. PubMed PMID: 10617673.

20: Sagot Y, Toni N, Perrelet D, Lurot S, King B, Rixner H, Mattenberger L, Waldmeier PC, Kato AC. An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease. Br J Pharmacol. 2000 Oct;131(4):721-8. PubMed PMID: 11030721; PubMed Central PMCID: PMC1572390.