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Omigapil
Omigapil (TCH346 or CGP3466) 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).〔(Santhera to Test Compound in CMD )〕〔(Santhera Pharmaceuticals: Development of SNT-317 (INN: omigapil) in CMD and other neuromuscular diseases )〕
Omigapil was first synthesized at Ciba-Geigy, 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.〔(【引用サイトリンク】title=Public summary of opinion on orphan designation: Omigapil maleate for the congenital muscular dystrophy with merosin (laminin alpha 2) deficiency )〕 Pharmacokinetic trials are scheduled to commence enrollment in the second half of 2012 to determine the appropriate pharmacokinetic profile of the drug for children with laminin-α2-deficient congenital muscular dystrophy (MDC1A) and collagen VI related myopathy. 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).〔(【引用サイトリンク】title=New collaboration to support omigapil clinical trial for congenital muscular dystrophy )〕
==Mechanism of action==
Omigapil inhibits programmed cell death (apoptosis) through the enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and SIAH1. The glycolytic housekeeping enzyme GAPDH is mediated by neuronal nitric oxide synthase. Once activated by nitric oxide, GAPDH binds to the ubiquitin ligase SIAH1, and is transported to the nucleus where it activates the acetyltransferases p300/CBP to enhance acetylation and subsequent transcription. GAPDH's targets proapoptotic genes such as p53, p53 upregulated modulator of apoptosis (PUMA), and p21 as well as other related targets. Chemogenetic studies indicate that omigapil inhibits this proapoptotic signaling cascade by preventing GAPDH activation through S-nitrosylation, which in turn prevents the binding of SIAH1 and translocation to the nucleus (see figure). Multiple binding cites on GAPDH have been suggested.
Omigapil was originally developed as a structurally similar molecule to selegiline (L-deprenyl), a monoamine oxidase inhibitor (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 (meth)amphetamine, which gives rise to adverse effects. Due to omigapil's tricyclic nature, the drug cannot be metabolized to amphetamine derivatives. Omigapil acts as a neuroprotective 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 ''in vivo'' and ''in vitro'' studies.
抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』
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