chemistry

Omigapil

Omigapil is a chemistry topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Omigapil rather than just read about it. In short: 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).

Key takeaways

Omigapil belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Omigapil to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Omigapil from memory before moving on to harder problems.

Reference excerpt

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). 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 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).

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.

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 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 cells from rotenone toxicity, β-amyloid toxicity, nutrition withdrawal, and lactacystin. 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 excitotoxicity and rat embryonic mesencephalic (midbrain) dopaminergic 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 axotomy animal models as well as mouse models of progressive motor neuronopathy, MPTP-induced nigrostriatal degeneration, and oxidopamine-induced neuronal injury. Omigapil also prevents the death of nigrostriatal 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 amyotrophic lateral sclerosis, 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

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Omigapil

Start with the simplest possible case. Write down what Omigapil claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Omigapil before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Omigapil ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Omigapil

In research: Omigapil appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Omigapil in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Omigapil is common in secondary-school and first-year university syllabi. It links to neighbouring topics Drugs acting on the nervous system, Drugs not assigned an ATC code, Orphan drugs, so understanding it makes those chapters shorter.
In everyday life: Look for Omigapil outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Omigapil in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Omigapil means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Omigapil out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Omigapil in simple terms?

Why does Omigapil matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Omigapil?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Omigapil.