219:
664:, but omigapil proved to be inefficacious for both diseases. It is unclear whether the discrepancy in results between laboratory studies and clinical studies is from improper pathogenesis modeling of the disease in animal models, insufficient doses of the study drug, insensitive clinical endpoints, or abnormal sampling in the patient population. However, the drug was determined to be safe for human use with no notable serious side effects.
401:. Santhera Pharmaceuticals will use the phase 1 clinical trial to determine if the drug is safe and acts with the same pharmacokinetic profile in children as it does in adults. The impending clinical trial will take place in the United States at the National Institute of Neurological Disorders and Stroke/National Institute of Health(NNDCS/NINDS) (Bethesda, Maryland) and in the United Kingdom at Great Ormond Street Hospital (UCL).
410:
31:
717:
in MDC1A mice. Omigapil coupled with mini-agrin overexpression works as a dual treatment that enhances mechanical load bearing ability and improves regeneration of muscle in MDC1A mice. Given that the technology for mini-agrin administration to skeletal muscle in human subjects is not yet available,
712:
The mouse model of laminin-α2-deficient congenital muscular dystrophy (MDC1A) was found to positively respond to omigapil with inhibition of apoptosis in muscle, reduction of body weight loss and skeletal deformation, increased locomotive activity, and protection from early mortality. Furthermore,
642:
dopaminergic neurons in monkeys treated with MPTP to mimic
Parkinson's disease symptoms. While omigapil was able to prevent programmed cell death for high-risk cells and prevent deterioration of concomitant motor deficits associated with Parkinson's symptoms, omigapil was unable to reverse
718:
omigapil is ready for human clinical trials to help mediate CMD. Omigapil has undergone extensive clinical trial scrutiny for
Parkinson's disease and ALS, which indicates that the drug is safe to begin clinical trials for congenital muscular dystrophy.
1252:
Waldmeier P, Bozyczko-Coyne D, Williams M, Vaught JL (November 2006). "Recent clinical failures in
Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases".
543:. In human trials for Parkinson's disease, doses of 0.5, 2.5 and 10 mg daily were considered, which resulted in the selection of a dose range of 0.3 to 3 mg daily for a 70 kg individual. Unfortunately a
992:
385:, Basel, Switzerland. Santhera Pharmaceuticals has since taken over production of omigapil and preclinical trials for CMD. In May 2008, omigapil was granted orphan designation to commence clinical trials for.
547:
has not been established for omigapil, which means that clinical trials rely on blood plasma levels to measure drug distribution rather than a validated biomarker to specifically measure brain exposure.
898:
Olanow CW, Schapira AH, LeWitt PA, Kieburtz K, Sauer D, Olivieri G, et al. (December 2006). "TCH346 as a neuroprotective drug in
Parkinson's disease: a double-blind, randomised, controlled trial".
753:
Olanow CW, Schapira AH, LeWitt PA, Kieburtz K, Sauer D, Olivieri G, et al. (December 2006). "TCH346 as a neuroprotective drug in
Parkinson's disease: a double-blind, randomised, controlled trial".
1799:
Andringa G, Eshuis S, Perentes E, Maguire RP, Roth D, Ibrahim M, et al. (November 2003). "TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates".
1386:
Andringa G, Eshuis S, Perentes E, Maguire RP, Roth D, Ibrahim M, et al. (November 2003). "TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates".
1611:
Erb M, Meinen S, Barzaghi P, Sumanovski LT, Courdier-Früh I, Rüegg MA, et al. (December 2009). "Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency".
1470:
Erb M, Meinen S, Barzaghi P, Sumanovski LT, Courdier-Früh I, Rüegg MA, et al. (December 2009). "Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency".
1018:
Hara MR, Agrawal N, Kim SF, Cascio MB, Fujimuro M, Ozeki Y, et al. (July 2005). "S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding".
685:") to peripheral neuropathy, inability to stand or walk, respiratory distress, and eventually premature death in early life. The majority of CMD cases result from a genetic mutation in
487:(MAO) blocking the enzyme MAO type B, yet omigapil inhibit neither type of MAO. Selegiline has proven problematic as a treatment for Parkinson's disease because it is metabolized to
556:
The compound displayed cell-rescuing effects in various models of apoptotic neuronal death, as well as in rodent and non-rodent animal models of neurodegeneration. Omigapil rescues
51:
996:
374:(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
1429:
Andringa G, Cools AR (2000). "The neuroprotective effects of CGP 3466B in the best in vivo model of
Parkinson's disease, the bilaterally MPTP-treated rhesus monkey".
713:
omigapil was found to be even more effective in improving muscle function and strength when coupled with overexpression of the extracellular matrix molecule mini-
1703:
Miller R, Bradley W, Cudkowicz M, Hubble J, Meininger V, Mitsumoto H, et al. (August 2007). "Phase II/III randomized trial of TCH346 in patients with ALS".
300:
499:
agent in cellular and rodent models of
Parkinson's disease like selegiline, but its neuroprotective action is 100 times more potent than selegiline in both
1862:
389:
trials are scheduled to commence enrollment in the second half of 2012 to determine the appropriate pharmacokinetic profile of the drug for children with
619:(PAJU) cells, omigapil can also prevent toxicity from rotenone and GAPDH overexpression. Omigapil has an active concentration range from about 10
426:
414:
975:"Public summary of opinion on orphan designation: Omigapil maleate for the congenital muscular dystrophy with merosin (laminin alpha 2) deficiency"
1857:
476:, which in turn prevents the binding of SIAH1 and translocation to the nucleus (see figure). Multiple binding cites on GAPDH have been suggested.
1580:
1563:
461:
1446:
1308:
1334:"An orally active anti-apoptotic molecule (CGP 3466B) preserves mitochondria and enhances survival in an animal model of motoneuron disease"
802:
for "A 12-Week, Multicenter, Safety and Dose-Ranging Study of 3 Oral Doses of TCH346 in
Patients With Amyotrophic Lateral Sclerosis" at
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320:
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96:
72:
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1206:"Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(-)-deprenyl"
678:
661:
375:
371:
1872:
178:
1291:
Waldmeier PC, Boulton AA, Cools AR, Kato AC, Tatton WG (2000). "Neurorescuing effects of the GAPDH ligand CGP 3466B".
484:
198:
1169:
Jenkins JL, Tanner JJ (March 2006). "High-resolution structure of human D-glyceraldehyde-3-phosphate dehydrogenase".
592:
943:"Santhera Pharmaceuticals: Development of SNT-317 (INN: omigapil) in CMD and other neuromuscular diseases"
682:
657:
540:
468:
as well as other related targets. Chemogenetic studies indicate that omigapil inhibits this proapoptotic
367:
681:(CMD) symptoms. This rare yet fatal infant disease has symptoms ranging from severe neonatal hypotonia ("
328:
InChI=1S/C19H17NO/c1-3-12-20(2)14-16-13-15-8-4-6-10-18(15)21-19-11-7-5-9-17(16)19/h1,4-11,13H,12,14H2,2H3
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438:
1123:
588:
1748:"Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation"
214:
620:
532:
520:
355:
113:
1656:"Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice"
842:"Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice"
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1593:
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to 10 M, with a maximum at about 10 M. Omigapil prevents neurodegeneration in facial
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Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler P, Muller D, et al. (March 1998).
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993:"New collaboration to support omigapil clinical trial for congenital muscular dystrophy"
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nature, the drug cannot be metabolized to amphetamine derivatives. Omigapil acts as a
363:
1812:
1399:
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Hara MR, Thomas B, Cascio MB, Bae BI, Hester LD, Dawson VL, et al. (March 2006).
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Sagot Y, Toni N, Perrelet D, Lurot S, King B, Rixner H, et al. (October 2000).
1061:
Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N, et al. (July 2008).
656:
Based on the preclinical results mentioned above, clinical trials were run for both
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624:
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10.1002/(SICI)1097-0029(20000201/15)48:3/4<181::AID-JEMT6>3.0.CO;2-Q
1433:. Journal of Neural Transmission. Supplementum. Vol. 60. pp. 215–225.
1295:. Journal of Neural Transmission. Supplementum. Vol. 60. pp. 197–214.
635:
572:
394:
30:
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Proceedings of the
National Academy of Sciences of the United States of America
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1063:"Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis"
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10.1002/(SICI)1097-0177(200006)218:2<213::AID-DVDY1>3.0.CO;2-R
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to block S-nitrosylation, thereby preventing proapoptotic gene expression.
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Omigapil was originally developed as a structurally similar molecule to
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Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Rüegg MA (August 2011).
1112:"Neuroprotection by pharmacologic blockade of the GAPDH death cascade"
840:
Meinen S, Lin S, Thurnherr R, Erb M, Meier T, Rüegg MA (August 2011).
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to enhance acetylation and subsequent transcription. GAPDH's targets
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in skeletal and heart muscle. The result is muscle degeneration and
693:-211 protein, which serves as an essential mechanical link between
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SIAH1, and is transported to the nucleus where it activates the
638:-induced neuronal injury. Omigapil also prevents the death of
465:
457:
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animal models as well as mouse models of progressive motor
1613:
The Journal of Pharmacology and Experimental Therapeutics
1472:
The Journal of Pharmacology and Experimental Therapeutics
491:, which gives rise to adverse effects. Due to omigapil's
1515:"Form and function: the laminin family of heterotrimers"
1746:
Harraz MM, Tyagi R, Cortés P, Snyder SH (March 2016).
441:. Once activated by nitric oxide, GAPDH binds to the
539:
dose was optimized between 0.014 and 0.14 mg/kg
393:-deficient congenital muscular dystrophy (MDC1A) and
643:pre-existing Parkinson's symptoms in MPTP monkeys.
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437:housekeeping enzyme GAPDH is mediated by neuronal
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587:in rat cortical neurons as well as toxicity from
104:Dibenzooxepin-10-ylmethyl-methyl-prop-2-ynylamine
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1379:
1377:
146:
1562:Miyagoe-Suzuki Y, Nakagawa M, Takeda S (2000).
634:, MPTP-induced nigrostriatal degeneration, and
121:
531:salt. Studies have demonstrated a bell-shaped
893:
891:
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8:
21:
1564:"Merosin and congenital muscular dystrophy"
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29:
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1431:Advances in Research on Neurodegeneration
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1293:Advances in Research on Neurodegeneration
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973:Committee for Orphan Medicinal Products.
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472:by preventing GAPDH activation through S-
421:Omigapil inhibits programmed cell death (
186:
535:for both rodent and primate models. The
427:glyceraldehyde 3-phosphate dehydrogenase
1513:Colognato H, Yurchenco PD (June 2000).
745:
325:
305:
213:
101:
462:p53 upregulated modulator of apoptosis
20:
575:. Additionally, omigapil can prevent
7:
736:-like rapid acting antidepressants.
571:toxicity, nutrition withdrawal, and
1210:The Journal of Biological Chemistry
137:
1863:Drugs acting on the nervous system
1717:10.1212/01.wnl.0000269676.07319.09
816:"Santhera to Test Compound in CMD"
381:Omigapil was first synthesized at
14:
1568:Microscopy Research and Technique
603:excitotoxicity and rat embryonic
308:C=3c1ccccc1Oc2ccccc2C=3CN(C)CC#C
252:
246:
1338:British Journal of Pharmacology
651:
333:Key:QLMMOGWZCFQAPU-UHFFFAOYSA-N
1858:Drugs not assigned an ATC code
519:Omigapil can pass through the
366:for its ability to help treat
255:
240:
1:
1813:10.1016/S0969-9961(03)00125-6
1400:10.1016/S0969-9961(03)00125-6
991:Muscular Dystrophy Campaign.
980:. EMA/COMP/204694/2008 Rev.1.
913:10.1016/S1474-4422(06)70602-0
768:10.1016/S1474-4422(06)70602-0
679:congenital muscular dystrophy
673:Congenital muscular dystrophy
662:amyotrophic lateral sclerosis
376:congenital muscular dystrophy
372:amyotrophic lateral sclerosis
1439:10.1007/978-3-7091-6301-6_14
1301:10.1007/978-3-7091-6301-6_13
595:. Omigapil also rescues rat
652:Parkinson's disease and ALS
485:monoamine oxidase inhibitor
1889:
230:Chemical and physical data
16:Drug developed by Novartis
1267:10.1016/j.bcp.2006.06.031
1183:10.1107/S0907444905042289
726:It has been investigated
552:Efficacy in animal models
316:
296:
92:
28:
1843:Santhera Pharmaceuticals
1255:Biochemical Pharmacology
677:Omigapil can ameliorate
593:cerebellar granule cells
1801:Neurobiology of Disease
1660:EMBO Molecular Medicine
1625:10.1124/jpet.109.160754
1484:10.1124/jpet.109.160754
1388:Neurobiology of Disease
1223:10.1074/jbc.273.10.5821
1137:10.1073/pnas.0511321103
846:EMBO Molecular Medicine
611:cells from toxicity by
1672:10.1002/emmm.201100151
1519:Developmental Dynamics
1350:10.1038/sj.bjp.0703633
858:10.1002/emmm.201100151
796:Clinical trial number
683:floppy infant syndrome
425:) through the enzymes
418:
358:that was developed by
901:The Lancet. Neurology
756:The Lancet. Neurology
439:nitric oxide synthase
412:
1752:Molecular Psychiatry
589:cytosine arabinoside
1873:Propargyl compounds
1764:10.1038/mp.2015.211
1128:2006PNAS..103.3887H
1067:Nature Cell Biology
1020:Nature Cell Biology
689:, a subunit of the
658:Parkinson's disease
533:dose-response curve
521:blood brain barrier
405:Mechanism of action
368:Parkinson's disease
25:
804:ClinicalTrials.gov
732:in the context of
447:acetyltransferases
419:
413:Omigapil binds to
1448:978-3-211-83537-1
1310:978-3-211-83537-1
1261:(10): 1197–1206.
1216:(10): 5821–5828.
1177:(Pt 3): 290–301.
1122:(10): 3887–3889.
907:(12): 1013–1020.
762:(12): 1013–1020.
707:peripheral nerves
695:basement membrane
527:as omigapil mono-
489:(meth)amphetamine
470:signaling cascade
341:
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287:Interactive image
199:CompTox Dashboard
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515:Pharmacokinetics
483:(L-deprenyl), a
443:ubiquitin ligase
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700:
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637:
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614:
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605:mesencephalic
602:
601:AMPA receptor
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625:motor neuron
615:. In human
609:dopaminergic
557:
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541:subcutaneous
518:
506:
500:
478:
464:(PUMA), and
454:proapoptotic
429:(GAPDH) and
420:
380:
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347:
343:
342:
73:Legal status
67:Legal status
18:
799:NCT00036413
636:oxidopamine
607:(midbrain)
591:(ara C) in
573:lactacystin
395:collagen VI
270: g·mol
123:181296-84-4
88:Identifiers
43:Other names
1852:Categories
959:2012-05-07
826:2011-09-18
740:References
722:Depression
687:laminin-α2
567:toxicity,
561:PC12 cells
481:selegiline
435:glycolytic
391:laminin-α2
383:Ciba-Geigy
275:3D model (
263:Molar mass
188:5V14HD0N4Q
159:ChemSpider
114:CAS Number
97:IUPAC name
1705:Neurology
613:MPP+/MPTP
583:receptor
569:β-amyloid
545:biomarker
511:studies.
493:tricyclic
423:apoptosis
370:(PD) and
1829:25987945
1821:14572443
1782:26782056
1733:29883238
1725:17709710
1690:21674808
1641:26038408
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776:17110281
734:ketamine
729:in vitro
668:Research
565:rotenone
558:in vitro
508:in vitro
450:p300/CBP
399:myopathy
397:related
360:Novartis
344:Omigapil
52:ATC code
23:Omigapil
1773:4830355
1681:3377088
1359:1572390
1232:9488718
1147:1450161
1124:Bibcode
1088:2689382
1048:1922911
929:1562331
867:3377088
784:1562331
691:laminin
628:axotomy
581:kainate
529:maleate
502:in vivo
378:(CMD).
354:) is a
352:CGP3466
268:275.351
236:Formula
168:4925351
148:6419718
134:PubChem
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301:SMILES
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1496:S2CID
1412:S2CID
1044:S2CID
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780:S2CID
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563:from
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415:GAPDH
321:InChI
277:JSmol
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1778:PMID
1721:PMID
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1537:PMID
1488:PMID
1453:PMID
1443:ISBN
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1093:PMID
1036:PMID
1005:2012
917:PMID
872:PMID
772:PMID
697:and
660:and
579:and
577:NMDA
505:and
356:drug
179:UNII
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1809:doi
1768:PMC
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1075:doi
1028:doi
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862:PMC
854:doi
764:doi
705:of
466:p21
458:p53
350:or
204:EPA
138:CID
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