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Darigabat
Clinical data
Other namesCVL-865; PF-06372865; PF-6372865
Routes of
administration		Oral administration
Drug classGABAA receptor positive allosteric modulator
Pharmacokinetic data
MetabolismCYP3A4[1]
Elimination half-life11 hours[1]
Identifiers
  • 7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC22H21FN4O3S
Molar mass440.49 g·mol−1
3D model (JSmol)
  • CCN1C=NC2=C1N=NC=C2C3=CC(=C(C=C3)F)C4=C(C=C(C=C4)S(=O)(=O)CC)OC
  • InChI=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
  • Key:PTTQXDBPTFOCMT-UHFFFAOYSA-N

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. ^ a b c Elkommos S, Mula M (December 2022). "Current and future pharmacotherapy options for drug-resistant epilepsy". Expert Opin Pharmacother. 23 (18): 2023–2034. doi:10.1080/14656566.2022.2128670. PMID 36154780. S2CID 252542159.
  2. ^ a b c d e f g "Darigabat - Cerevel Therapeutics - AdisInsight".
  3. ^ a b c d e f g h i j Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, Golani LK, Cook JM, Witkin JM (June 2022). "GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors". Pharmacol Ther. 234: 108035. doi:10.1016/j.pharmthera.2021.108035. PMC 9787737. PMID 34793859.
  4. ^ a b c d 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 (February 2022). "The imidazodiazepine, KRM-II-81: An example of a newly emerging generation of GABAkines for neurological and psychiatric disorders". Pharmacol Biochem Behav. 213: 173321. doi:10.1016/j.pbb.2021.173321. PMID 35041859. S2CID 245963990.
  5. ^ a b c d Quagliato LA, Carta MG, Nardi AE (2022). "Panic Disorder Seeks More Specific Drugs for Treatment: Might the Amygdala Be the Best Target?". J Clin Psychopharmacol. 42 (5): 427–428. doi:10.1097/JCP.0000000000001591. PMID 36099401. S2CID 252219658.
  6. ^ a b Janković SM, Dješević M, Janković SV (2021). "Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy". J Exp Pharmacol. 13: 235–244. doi:10.2147/JEP.S242964. PMC 7954424. PMID 33727865.

External links

GABAA receptor positive modulators
Categories