PF-06372865   Click here for help

GtoPdb Ligand ID: 9798

Synonyms: darigabat (proposed INN) | example 4 [WO2014091368] | PF06372865
Compound class: Synthetic organic
Comment: PF-06372865 is an orally active, GABAA receptor positive allosteric modulator, that selectively targets GABAA receptors containing α2/3/5 subunits over receptors containing α1 subunits [1,3]. The α1 subunit is associated with the (undesirable) sedative effects of benzodiazepine drugs, whilst the α2/3 subunits contribute to their anxiolytic and analgesic activities and the α5 subunit to effects on memory function. The chemical structure of PF-06372865 is claimed as 'Example 4' in patent WO2014091368 [2]. Pfizer are developing PF-06372865 for clinical potential in the treatment of chronic pain [4] and photosensitive epilepsy, but have terminated development in generalized anxiety disorder.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 0
Rotatable bonds 6
Topological polar surface area 95.35
Molecular weight 440.13
XLogP 4.53
No. Lipinski's rules broken 0
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Canonical SMILES COc1cc(ccc1c1cc(ccc1F)c1cnnc2c1ncn2CC)S(=O)(=O)CC
Isomeric SMILES COc1cc(ccc1c1cc(ccc1F)c1cnnc2c1ncn2CC)S(=O)(=O)CC
InChI 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
1. Nickolls SA, Gurrell R, van Amerongen G, Kammonen J, Cao L, Brown AR, Stead C, Mead A, Watson C, Hsu C et al.. (2018)
Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865.
Br. J. Pharmacol., 175 (4): 708-725. [PMID:29214652]
2. Omoto K, Owen RM, Pryde DC, Watson CAL, Takeuchi M. (2014)
Imidazopyridazine derivatives as GABAA receptor modulators.
Patent number: WO2014091368. Assignee: Pfizer Limited. Priority date: 14/12/2012. Publication date: 19/06/2014.
3. Owen RM, Blakemore D, Cao L, Flanagan N, Fish R, Gibson KR, Gurrell R, Huh CW, Kammonen J, Mortimer-Cassen E et al.. (2019)
Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865).
J. Med. Chem., 62 (12): 5773-5796. [PMID:30964988]
4. van Amerongen G, Siebenga PS, Gurrell R, Dua P, Whitlock M, Gorman D, Okkerse P, Hay JL, Butt RP, Groeneveld GJ. (2019)
Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABAA partial agonist, in humans.
Br J Anaesth, 123 (2): e194-e203. [PMID:30915991]