Repositioning Candidate Details
| Candidate ID: | R0083 |
| Source ID: | DB00313 |
| Source Type: | approved; investigational |
| Compound Type: | small molecule |
| Compound Name: | Valproic acid |
| Synonyms: | |
| Molecular Formula: | C8H16O2 |
| SMILES: | CCCC(CCC)C(O)=O |
| Structure: |
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| DrugBank Description: | Valproic acid, or valproate, is an fatty acid derivative and anticonvulsant originally synthesized in 1881 by Beverly S. Burton.[A178051] It enjoyed use as a popular organic solvent in industry and pharmaceutical manufacturing for nearly a century. In 1963, a serendipitous discovery was made by George Carraz during his investigations into the anticonvulsant effects of khelline when he found that all of his samples, dissolved in valproic acid, exerted a similar degree of anticonvulsive activity. It first received approval on February 28, 1978 from the FDA under the trade name Depakene.[L6190] Since then, it has been investigated for neuroprotective, anti-manic, and anti-migraine effects. It is currently a compound of interest in the field of oncology for its anti-proliferative effects and is the subject of many clinical trials in a variety of cancer types. |
| CAS Number: | 99-66-1 |
| Molecular Weight: | 144.2114 |
| DrugBank Indication: | **Indicated** for:[Label] 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. **Off-label** uses include: 1) Maintenance therapy for bipolar disorder.[A177919] 2) Treatment for acute bipolar depression.[A177928,A177931,A177934] 3) Emergency treatment of status epilepticus.[A177955] |
| DrugBank Pharmacology: | Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches.[FDA Label,A177841] It also improves symptom control in bipolar mania.[A178033] Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug.[A457] A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART.[A458,A177859] The FDA labeling contains a warning regarding HIV reactivation during valproate use.[label]. |
| DrugBank MoA: | The exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase.[A177991] This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity.[A457] A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK).[A457] These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA<sub>A</sub> receptors which contribute further to increased GABAergic activity.[A177997] Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase.[A178000] This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect.[A178003] Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium.[A178015] The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis.[A178018] Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton.[A178021] Valproate also appears to impact fatty acid metabolism.[A457] Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action.[A178024] Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase.[A14708] Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor.[A178030] Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated.[A178027] The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients.[A178033] Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong.[A178036] H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective effects.[A11814] |
| Targets: | Histone deacetylase 9; Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial; 2-oxoglutarate dehydrogenase, mitochondrial; Succinate-semialdehyde dehydrogenase, mitochondrial; Sodium channel protein; Histone deacetylase 2; Peroxisome proliferator-activated receptor alpha; Peroxisome proliferator-activated receptor delta; Peroxisome proliferator-activated receptor gamma; Histone deacetylase; Cyclin-dependent kinase inhibitor 1; Hepatocyte growth factor; Ornithine decarboxylase; Programmed cell death 1 ligand 1 |
| Inclusion Criteria: |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs | |
|---|---|---|---|---|---|
| S07 | antihypertensive | Anti-fibrosis; Anti-hypertensive; Anti-hypertensive; antihypertensive medications; multidrug combination antihypertensive treatment; empirical addition (or increase in the dose) of an antihypertensive agent of a different class""; Anti-hypertensive; Lifestyle measures; Anti-inflammatory; Improve insulin resistance; Enhance lipid metabolism; Regulating intestinal flora; Anti-hypertensive; Anti-hypertensive; Anti-inflammatory; Anti-fibrosis; Anti-inflammatory; Immunotherapy; Anti-hypertensive; Immunosuppressive treatment; Anti-hypertensive; Anti-hypertensive; Anti-platelet aggregation; other antihypertensive drugs; antihypertensive therapy; Anti-hypertensive; Anti-inflammatory; Anti-hypertensive (standard antihypertensive treatment; intensive antihypertensive treatment); Blood pressure management; Anti-hypertensive; Enhance lipid metabolism; Anti-hypertensive; Enhance lipid metabolism; Anti-platelet aggregation; Improve insulin resistance; Anti-hypertensive; Anti-hypertensive; Anti-oxidative stress; antihypertensives; Lifestyle measures; Anti-hypertensive; Anti-fibrosis; Anti-inflammatory; Anti-hypertensive | ACE; Smad4; PKD1; angiotensin receptor; SGLT2; angiotensin II receptor; mineralocorticoid receptor; ACE | riociguat; sGC stimulators; sGC activators; antihypertensive medications; carvedilol; lercanidipine; enalapril; folic acid; retinoic acid; angiotensin II; antihypertensive drug; Tripterygium Wilfordii Hook F; valsartan; Renin-angiotensin system inhibitors; diuretics; calcium channel blocker; corticosteroid; anti-hypertensive treatment; NSAIDs; naproxen; celecoxib; proton pump inhibitor; non-selective NSAID; selective cyclo-oxygenase-2 inhibitor; renin-angiotensin system blockers; antihypertensive agent; cilnidipine; valsartan; RAAS-is; steroids; immunosuppressors; amiloride; hydrochlorothiazide; berberine; Aliskiren; calcium channel blocker; angiotensin II receptor blocker; ARB; Chlorthalidone; Hydrochlorothiazide; Hsub2/subS; NO; Hsub2/subSxa0; xa0; NO; prednisolone; mizoribine; angiotensin-converting enzyme inhibitors; ACEI; eculizumab; antihypertensive agents; antithrombotics; antianemics; proton pump inhibitors; allopurinol; rilmenidine; long-term benzodiazepines; anticholinergic drugs; hydroxyzine; Qian Yang Yu Yin Granule; RAAS blockers; other antihypertensive drugs; antihypertensives; antihypertensive classes; antihypertensive therapy; melatonin; RAASi; Aliskiren; ARBs; ACEIs; tegafur/gimeracil/oteracil; furosemide; prednisolone; angiotensin receptor blockers; valsartan; antihypertensive drugs; fosinopril; valsartan; Canagliflozin; sodium glucose co-transporter 2 inhibitors; Aspirin; Antihypertensive; Lipid-Lowering Treatment; Sodium-glucose cotransporter 2 inhibitors; angiotensin II receptor blocker; Spironolactone; KBP-5074; captopril; enalaprilate; lisinopril; losartan; valsartan; furosemide; pravastatin; simvastatin; Renin Angiotensin System inhibitors; ACE inhibitors; diuretics; β-blockers; Thiazide diuretics; dihydropyridine calcium-channel blockers; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers; calcium-channel blockers; thiazide-like diuretics; lisinopril; Edarbyclor; azilsartan medoxomil; chlorthalidone; hydrochlorothiazide; aliskiren; ARB; enalapril; non-steroidalanti-inflammatory drugs; antihypertensive treatment; Chlorthalidone; loop diuretics; angiotensin-converting enzyme inhibitor; angiotensin receptor blocker; statin; captopril; tiopronin; active form of dalcetrapib; active metabolite of prasugrel, R-138727; Liuwei Dihuang pills; metformin hydrochloride sustained-release tablets; irbesartan tablets; renin-angiotensin-aldosterone system inhibitor; type 1 angiotensin II receptor blockade; olmesartan; steroid; immunosuppressive agents; enalapril; corticosteroid treatment; Angiotensin-converting-enzyme inhibitors; antihypertensives; GLP-1 receptor analogue; SGLT2-inhibitor; sacubitril/valsartan; valsartan; Sulodexide; liraglutide; enalapril; ACE-I/ARBs; angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers; labetalol; ACEi; ARB; ARBs | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name | |
|---|---|---|---|---|---|---|---|
| T47 | Sialin | SLC17A5 | Target is a single protein chain | Q9NRA2 | SLC17A5_HUMAN | Details | |
| T06 | Sulfonylurea receptor 1 | ABCC8 | Target is a single protein chain | Q09428 | ABCC8_HUMAN | Details | |
| T15 | Steryl-sulfatase | STS | INHIBITOR | Hydrolase | P08842 | STS_HUMAN | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I02 | 1184 | nephrotic syndrome | "A nephrosis characterized by marked increase in glomerular protein permeability resulting in marked elevation of urine protein levels, hypoalbuminemia, hyperlipidemia, and hypercoagulability." [url:https\://en.wikipedia.org/wiki/Nephrotic_syndrome, url:https\://www.niddk.nih.gov/health-information/kidney-disease/nephrotic-syndrome-adults] | Details |