Omigapil (TCH346 or CGP3466) is a

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

that was developed by Novartis and tested in clinical trials for its ability to help treat Parkinson's disease (PD) and

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(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 Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges fro ...

(CMD). 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.

Pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

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 In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...

. 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).

Mechanism of action

Omigapil inhibits programmed cell death (

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

) through the enzymes

glyceraldehyde 3-phosphate dehydrogenase Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establishe ...

(GAPDH) and

SIAH1 E3 ubiquitin-protein ligase SIAH1 is an enzyme that in humans is encoded by the ''SIAH1'' gene. Function This gene encodes for a polypeptide structure that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase ...

. The

glycolytic Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

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

acetyltransferase Acetyltransferase (or transacetylase) is a type of transferase enzyme that transfers an acetyl group. Examples include: * Histone acetyltransferases including CBP histone acetyltransferase * Choline acetyltransferase * Chloramphenicol acetyltransf ...

p300/CBP The p300-CBP coactivator family in humans is composed of two closely related transcriptional co-activating proteins (or coactivators): #p300 (also called EP300 or E1A binding protein p300) # CBP (also known as CREB-binding protein or CREBBP) ...

to enhance acetylation and subsequent transcription. GAPDH's targets proapoptotic genes such as p53,

p53 upregulated modulator of apoptosis The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the ''BBC3'' gene. ...

(PUMA), and

p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...

as well as other related targets. Chemogenetic studies indicate that omigapil inhibits this proapoptotic

signaling cascade A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...

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 Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...

(L-deprenyl), a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...

(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.

Pharmacokinetics

Omigapil can pass through the blood brain barrier and has oral bioavailability as omigapil mono- maleate salt. Studies have demonstrated a bell-shaped dose-response curve for both rodent and primate models. The

rhesus monkey The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...

dose was optimized between 0.014 and 0.14 mg/kg subcutaneous. 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 biomarker 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.

Efficacy in animal models

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 ''in vitro''

PC12 cell PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla, that have an embryonic origin from the neural crest that has a mixture of neuroblastic cells and eosinophilic cells. Background This cell line was first cultured ...

s from rotenone toxicity, β-amyloid toxicity, nutrition withdrawal, and

lactacystin Lactacystin is an organic compound naturally synthesized by bacteria of the genus '' Streptomyces'' first identified as an inducer of neuritogenesis in neuroblastoma cells in 1991.Omura S, Fujimoto T, Otoguro K, Matsuzaki K, Moriguchi R, Tanaka H ...

. Additionally, omigapil can prevent NMDA and kainate receptor excitotoxicity in rat cortical neurons as well as toxicity from cytosine arabinoside (ara C) in cerebellar granule cells. Omigapil also rescues rat oligodendrocytes from

AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...

excitotoxicity and rat embryonic

mesencephalic The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...

(midbrain)

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...

cells from toxicity by MPP+/MPTP. In human neuroblastoma (PAJU) cells, omigapil can also prevent toxicity from rotenone and GAPDH overexpression. Omigapil has an active concentration range from about 10⁻¹² M to 10⁻⁵ M, with a maximum at about 10⁻⁹ M. Omigapil prevents neurodegeneration in facial

motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...

axotomy An axotomy is the cutting or otherwise severing of an axon. Derived from axo- (=axon) and -tomy (=surgery). This type of denervation is often used in experimental studies on neuronal physiology and neuronal death or survival as a method to better u ...

animal models as well as mouse models of progressive motor

neuronopathy Polyneuropathy ( poly- + neuro- + -pathy) is damage or disease affecting peripheral nerves (peripheral neuropathy) in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hand ...

, MPTP-induced nigrostriatal degeneration, and

oxidopamine Oxidopamine, also known as 6-hydroxydopamine (6-OHDA) or 2,4,5-trihydroxyphenethylamine, is a neurotoxic synthetic organic compound used by researchers to selectively destroy dopaminergic and noradrenergic neurons in the brain. The main use for o ...

-induced neuronal injury. Omigapil also prevents the death of

nigrostriatal The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum (i.e., the caudate nucleus and putamen) in the forebrain. It is one of the fo ...

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 pre-existing Parkinson's symptoms in MPTP monkeys.

Clinical trials

Parkinson's disease and ALS

Based on the preclinical results mentioned above, clinical trials were run for both Parkinson's disease and

, 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.

Research

Congenital muscular dystrophy

Omigapil can ameliorate

(CMD) symptoms. This rare yet fatal infant disease has symptoms ranging from severe neonatal hypotonia ("

floppy infant syndrome Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

") 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 laminin-α2, a subunit of the laminin-211 protein, which serves as an essential mechanical link between

basement membrane The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...

and muscle fiber in skeletal and heart muscle. The result is muscle degeneration and demyelination of peripheral nerves. 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, omigapil was found to be even more effective in improving muscle function and strength when coupled with overexpression of the extracellular matrix molecule mini- agrin 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, 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.

Depression

It has been investigated '' in vitro'' in the context of ketamine-like rapid acting antidepressants.

References

External links

Santhera Pharmaceuticals
Drugs acting on the nervous system Orphan drugs Propargyl compounds