darigabat

{{Short description|Chemical compound}}

{{Lead rewrite|date=August 2023}}

{{Infobox drug

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| routes_of_administration = Oral administration

| class = GABA_A receptor positive allosteric modulator

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| metabolism = CYP3A4

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| elimination_half-life = 11 hours

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| CAS_number = 1614245-70-3

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| PubChem = 76287260

| IUPHAR_ligand = 9798

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| ChemSpiderID = 58950370

| UNII = O9BP19HZ3Q

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| ChEMBL = 3647536

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| synonyms = CVL-865; PF-06372865; PF-6372865

| IUPAC_name = 7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine

| C=22 | H=21 | F=1 | N=4 | O=3 | S=1

| SMILES = CCN1C=NC2=C1N=NC=C2C3=CC(=C(C=C3)F)C4=C(C=C(C=C4)S(=O)(=O)CC)OC

| StdInChI = 1S/C22H21FN4O3S/c1-4-27-13-24-21-18(12-25-26-22(21)27)14-6-9-19(23)17(10-14)16-8-7-15(11-20(16)30-3)31(28,29)5-2/h6-13H,4-5H2,1-3H3

| StdInChIKey = PTTQXDBPTFOCMT-UHFFFAOYSA-N

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Darigabat (developmental code names CVL-865, PF-06372865, PF-6372865) is a GABAergic medication which is under development for the treatment of photosensitive epilepsy, focal onset seizures, panic disorder, and other anxiety disorders.{{cite web | url=https://adisinsight.springer.com/drugs/800039009 | title=Darigabat - Cerevel Therapeutics - AdisInsight }} It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued.{{cite journal | vauthors = Witkin JM, Lippa A, Smith JL, Jin X, Ping X, Biggerstaff A, Kivell BM, Knutson DE, Sharmin D, Pandey KP, Mian MY, Cook JM, Cerne R | title = The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders | journal = Pharmacol Biochem Behav | volume = 213 | issue = | pages = 173321 | date = February 2022 | pmid = 35041859 | doi = 10.1016/j.pbb.2021.173321 | s2cid = 245963990 | url = | doi-access = free }} It is taken via oral administration.

Darigabat acts as a GABA_A receptor positive allosteric modulator It is specifically a positive allosteric modulator that selectively targets α₂, α₃, and α₅ subunit-containing GABA_A receptors, with minimal functional activity at α₁ subunit-containing GABA_A receptors.{{cite journal | vauthors = Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, Golani LK, Cook JM, Witkin JM | title = GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors | journal = Pharmacol Ther | volume = 234 | issue = | pages = 108035 | date = June 2022 | pmid = 34793859 | doi = 10.1016/j.pharmthera.2021.108035 | pmc = 9787737 | url = }}{{cite journal | vauthors = Quagliato LA, Carta MG, Nardi AE | title = Panic Disorder Seeks More Specific Drugs for Treatment: Might the Amygdala Be the Best Target? | journal = J Clin Psychopharmacol | volume = 42 | issue = 5 | pages = 427–428 | date = 2022 | pmid = 36099401 | doi = 10.1097/JCP.0000000000001591 | s2cid = 252219658 | url = }} A dose of darigabat that achieved more than 80% receptor occupancy showed no somnolence with dose titration, whereas benzodiazepines, which are non-selective GABA_A receptor positive allosteric modulators, achieve only 10 to 15% receptor occupancy whilst producing significant or severe somnolence. It is theorized that α₁ subunit-containing GABA_A receptors preferentially mediate sedation, amnesia, and ataxia, whereas α₂ and α₃ subunit-containing GABA_A receptors mediate anxiolysis. However, this model has also been questioned. α₁ subunit-containing GABA_A receptors are said to be completely unaffected by darigabat.{{cite journal | vauthors = Janković SM, Dješević M, Janković SV | title = Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy | journal = J Exp Pharmacol | volume = 13 | issue = | pages = 235–244 | date = 2021 | pmid = 33727865 | pmc = 7954424 | doi = 10.2147/JEP.S242964 | url = | doi-access = free }} The elimination half-life of darigabat is 11{{nbsp}}hours and it is metabolized mainly by CYP3A4.{{cite journal | vauthors = Elkommos S, Mula M | title = Current and future pharmacotherapy options for drug-resistant epilepsy | journal = Expert Opin Pharmacother | volume = 23 | issue = 18 | pages = 2023–2034 | date = December 2022 | pmid = 36154780 | doi = 10.1080/14656566.2022.2128670 | s2cid = 252542159 | url = }}

In clinical trials conducted thus far, side effects of darigabat have included dizziness, fatigue, headache, mild-to-moderate somnolence, bradyphrenia (slowness of thought), modest memory impairment, mild cognitive impairment, balance impairment, and feeling abnormal. It has been described as well-tolerated.

Darigabat was originated by Pfizer and is under development by Cerevel Therapeutics and Pfizer. As of January 2023, it is in phase 2 clinical trials for epilepsy and seizures, phase 1 trials for panic disorder, and preclinical development for anxiety disorders. Development for back pain was discontinued due to lack of effectiveness in a phase 2 trial, while development for generalized anxiety disorder was discontinued due to business reasons as well as lack of effectiveness in a phase 2 trial.