Chemistry:Darigabat
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| Other names | CVL-865; PF-06372865; PF-6372865 |
| Routes of administration | Oral administration |
| Drug class | GABAA receptor positive allosteric modulator |
| Pharmacokinetic data | |
| Metabolism | CYP3A4[1] |
| Elimination half-life | 11 hours[1] |
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| Chemical and physical data | |
| Formula | C22H21FN4O3S |
| Molar mass | 440.49 g·mol−1 |
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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.[2][3] It was also under development for the treatment of generalized anxiety disorder and chronic lower back pain, but development for these indications was discontinued.[2][3][4] It is taken via oral administration.[2]
Darigabat acts as a GABAA receptor positive allosteric modulator, also known as a GABAkine.[2][3][5] It is specifically a positive allosteric modulator that selectively targets α2, α3, and α5 subunit-containing GABAA receptors, with minimal functional activity at α1 subunit-containing GABAA receptors.[3][5] A dose of darigabat that achieved more than 80% receptor occupancy showed no somnolence with dose titration, whereas benzodiazepines, which are non-selective GABAA receptor positive allosteric modulators, achieve only 10 to 15% receptor occupancy whilst producing significant or severe somnolence.[3][5] It is theorized that α1 subunit-containing GABAA receptors preferentially mediate sedation, amnesia, and ataxia, whereas α2 and α3 subunit-containing GABAA receptors mediate anxiolysis.[3][5] However, this model has also been questioned.[4] α1 subunit-containing GABAA receptors are said to be completely unaffected by darigabat.[6] The elimination half-life of darigabat is 11 hours and it is metabolized mainly by CYP3A4.[1]
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.[3][6] It has been described as well-tolerated.[3][4]
Darigabat was originated by Pfizer and is under development by Cerevel Therapeutics and Pfizer.[2] 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.[2][3] 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.[3][4][2]
See also
References
- ↑ 1.0 1.1 1.2 "Current and future pharmacotherapy options for drug-resistant epilepsy". Expert Opin Pharmacother 23 (18): 2023–2034. December 2022. doi:10.1080/14656566.2022.2128670. PMID 36154780.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Darigabat - Cerevel Therapeutics - AdisInsight". https://adisinsight.springer.com/drugs/800039009.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 "GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors". Pharmacol Ther 234: 108035. June 2022. doi:10.1016/j.pharmthera.2021.108035. PMID 34793859.
- ↑ 4.0 4.1 4.2 4.3 "The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders". Pharmacol Biochem Behav 213: 173321. February 2022. doi:10.1016/j.pbb.2021.173321. PMID 35041859.
- ↑ 5.0 5.1 5.2 5.3 "Panic Disorder Seeks More Specific Drugs for Treatment: Might the Amygdala Be the Best Target?". J Clin Psychopharmacol 42 (5): 427–428. 2022. doi:10.1097/JCP.0000000000001591. PMID 36099401.
- ↑ 6.0 6.1 "Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy". J Exp Pharmacol 13: 235–244. 2021. doi:10.2147/JEP.S242964. PMID 33727865.
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