Darigabat

Last updated
Darigabat
Darigabat.png
Clinical data
Other namesCVL-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]
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
Formula C22H21FN4O3S
Molar mass 440.49 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]

Contents

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

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