| Routes Of Administration: | Oral administration |
| Class: | GABAA receptor positive allosteric modulator |
| Metabolism: | CYP3A4 |
| Elimination Half-Life: | 11 hours |
| Cas Number: | 1614245-70-3 |
| Pubchem: | 76287260 |
| Iuphar Ligand: | 9798 |
| Chemspiderid: | 58950370 |
| Unii: | O9BP19HZ3Q |
| Chembl: | 3647536 |
| 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 |
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.[1] 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] It is taken via oral administration.
Darigabat acts as a GABAA receptor positive allosteric modulator 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] [4] 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. 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. However, this model has also been questioned. α1 subunit-containing GABAA receptors are said to be completely unaffected by darigabat.[5] The elimination half-life of darigabat is 11hours and it is metabolized mainly by CYP3A4.[6]
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.