DHA-clozapine

Last updated
DHA-clozapine
Docosahexaenoyl-clozapine.svg
Clinical data
Trade names Clozaprexin
Other namesDocosahexaenoyl clozapine
ATC code
  • none
Legal status
Legal status
Identifiers
  • (4Z,7Z,10Z,13Z,16Z,19Z)-1-[3-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzodiazepin-11-yl]docosa-4,7,10,13,16,19-hexaen-1-one
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C40H49ClN4O
Molar mass 637.31 g·mol−1
3D model (JSmol)
  • Clc1ccc2N(C(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC)c4ccccc4C(=N/c2c1)\N3CCN(C)CC3
  • InChI=1S/C40H49ClN4O/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-26-39(46)45-37-25-23-22-24-35(37)40(44-31-29-43(2)30-32-44)42-36-33-34(41)27-28-38(36)45/h4-5,7-8,10-11,13-14,16-17,19-20,22-25,27-28,33H,3,6,9,12,15,18,21,26,29-32H2,1-2H3/b5-4-,8-7-,11-10-,14-13-,17-16-,20-19- X mark.svgN
  • Key:RPSJOJIGGSRDMO-JDPCYWKWSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

DHA-clozapine (tentative trade name Clozaprexin) [1] is an atypical antipsychotic drug candidate that was created and originally tested by chemists at Protarga, a small pharmaceutical in Pennsylvania, and scientists at Harvard University. [2]

It is a prodrug of clozapine; the fatty acid docosahexaenoic acid (DHA) was added to clozapine in order to increase penetration of the blood–brain barrier. [3]

Protarga was purchased by Luitpold Pharmaceuticals in 2003 and development was discontinued in 2007. [1]


Related Research Articles

Omega−3 fatty acids, also called Omega-3 oils, ω−3 fatty acids or n−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chemical structure. They are widely distributed in nature, being important constituents of animal lipid metabolism, and they play an important role in the human diet and in human physiology. The three types of omega−3 fatty acids involved in human physiology are α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA can be found in plants, while DHA and EPA are found in algae and fish. Marine algae and phytoplankton are primary sources of omega−3 fatty acids. DHA and EPA accumulate in fish that eat these algae. Common sources of plant oils containing ALA include walnuts, edible seeds, and flaxseeds, while sources of EPA and DHA include fish and fish oils, as well as algae oil.

<span class="mw-page-title-main">Clozapine</span> Atypical antipsychotic medication

Clozapine is a psychiatric medication and is the first atypical antipsychotic. It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or who have been unable to tolerate other drugs due to extrapyramidal side effects. It is also used for the treatment of psychosis in Parkinson's disease. Clozapine is regarded as the gold-standard treatment when other medication has been insufficiently effective and its use is recommended by multiple international treatment guidelines, after resistance to earlier neuroleptic treatment is established.

Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health but cannot synthesize them.

<span class="mw-page-title-main">Arachidonic acid</span> Fatty acid used metabolically in many organisms

Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word arachis (peanut), but peanut oil does not contain any arachidonic acid.

<span class="mw-page-title-main">Cytochrome P450</span> Class of enzymes

Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown. In 1963, Estabrook, Cooper, and Rosenthal described the role of CYP as a catalyst in steroid hormone synthesis and drug metabolism. In plants, these proteins are important for the biosynthesis of defensive compounds, fatty acids, and hormones.

Krill oil is an extract prepared from a species of Antarctic krill, Euphausia superba. Processed krill oil is commonly sold as a dietary supplement. Two components of krill oil are omega-3 fatty acids similar to those in fish oil, and phospholipid-derived fatty acids (PLFA), mainly phosphatidylcholine.

<span class="mw-page-title-main">Fish oil</span> Oil derived from the tissues of oily fish

Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation in the body and improve hypertriglyceridemia. There has been a great deal of controversy in recent years about the role of fish oil in cardiovascular disease, with recent meta-analyses reaching different conclusions about its potential impact. The most promising evidence supports supplementation for prevention of cardiac death.

<span class="mw-page-title-main">Eicosapentaenoic acid</span> Chemical compound

Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-carbon chain and five cis double bonds; the first double bond is located at the third carbon from the omega end.

DHA, Dha and dha may refer to:

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk, fatty fish, fish oil, or algae oil.

<span class="mw-page-title-main">Free fatty acid receptor 1</span> Protein-coding gene in the species Homo sapiens

Free fatty acid receptor 1 (FFA1), also known as GPR40, is a class A G-protein coupled receptor that in humans is encoded by the FFAR1 gene. It is strongly expressed in the cells of the pancreas and to a lesser extent in the brain. This membrane protein binds free fatty acids, acting as a nutrient sensor for regulating energy homeostasis.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

<span class="mw-page-title-main">Omega-3 acid ethyl esters</span>

Omega-3-acid ethyl esters are a mixture of ethyl eicosapentaenoic acid and ethyl docosahexaenoic acid, which are ethyl esters of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil. Together with dietary changes, they are used to treat high blood triglycerides which may reduce the risk of pancreatitis. They are generally less preferred than statins, and use is not recommended by NHS Scotland as the evidence does not support a decreased risk of heart disease. Omega-3-acid ethyl esters are taken by mouth.

<span class="mw-page-title-main">Ethyl eicosapentaenoic acid</span>

Ethyl eicosapentaenoic acid, sold under the brand name Vascepa among others, is a medication used to treat dyslipidemia and hypertriglyceridemia. It is used in combination with changes in diet in adults with hypertriglyceridemia ≥ 150 mg/dL. Further, it is often required to be used with a statin.

Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had two US approvals for advanced cancers.

<span class="mw-page-title-main">Desmethylclozapine</span> Chemical compound

N-Desmethylclozapine (NDMC), or norclozapine, is a major active metabolite of the atypical antipsychotic drug clozapine. Unlike clozapine, it possesses intrinsic activity at the D2/D3 receptors, and acts as a weak partial agonist at these sites similarly to aripiprazole and bifeprunox. Notably, NDMC has also been shown to act as a potent and efficacious agonist at the M1 and δ-opioid receptors, unlike clozapine as well. It was hypothesized that on account of these unique actions, NDMC might underlie the clinical superiority of clozapine over other antipsychotics. However, clinical trials found NMDC itself ineffective in the treatment of schizophrenia. This may be because it possesses relatively low D2/D3 occupancy compared to 5-HT2 (<15% versus 64-79% at a dose of 10–60 mg/kg s.c. in animal studies). Albeit not useful in the treatment of positive symptoms on its own, it cannot be ruled out that NDMC may contribute to the efficacy of clozapine on cognitive and/or negative symptoms.

GPR 120 is a G protein-coupled receptor (GPCR) and the putative receptor for omega-3 fatty acids including Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA). GPR 120 was among a number of free fatty acid receptors only recently discovered from the human genome database utilizing the GPCR deorphanizing strategy. Binding to the GPR 120 receptor is one of the many putative mechanisms of action for the potential health benefits of consuming omega-3 fatty acids. GPR 120 has specifically shown a role in the in-vivo anti-inflammatory and insulin-sensitizing effects of DHA and EPA in macrophages. Macrophage mediated inflammation is a key player in the pathophysiology of metabolic syndrome related disorders, including diabetes and atherosclerosis. GPR 120 is also a key regulator of adipogenesis, including adipocyte development and differentiation.

Omega-3 carboxylic acids (Epanova) is a formerly-marketed yet still FDA approved prescription medication–since taken off market by the manufacturer–used alongside a low fat and low cholesterol diet that lowers high triglyceride (fat) levels in adults with very high levels. This was the third class of fish oil-based drug, after omega-3 acid ethyl esters and ethyl eicosapentaenoic acid (Vascepa), to be approved for use as a drug. The first approval by US Food and Drug Administration was granted 05 May 2014. These fish oil drugs are similar to fish oil dietary supplements, but the ingredients are better controlled and have been tested in clinical trials. Specifically, Epanova contained at least 850 mg omega-3-acid ethyl esters per 1 g capsule.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acid's (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, Vicinal (chemistry) dihydroxy fatty acids by ubiquitous cellular Soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

References

  1. 1 2 "DHA-clozapine". AdisInsight. Retrieved 17 March 2017.
  2. Rosack, Jim (4 May 2001). "Targaceuticals Point Way To Developing Safer Drugs". Psychiatric News. 36 (9): 36–37. doi:10.1176/pn.36.9.0036.
  3. Baldessarini RJ, Campbell A, Webb NL, Swindell CS, Flood JG, Shashoua VE, et al. (January 2001). "Fatty acid derivatives of clozapine: prolonged antidopaminergic activity of docosahexaenoylclozapine in the rat". Neuropsychopharmacology. 24 (1): 55–65. doi: 10.1016/S0893-133X(00)00173-1 . PMID   11106876.