In:
British Journal of Pharmacology, Wiley, Vol. 175, No. 4 ( 2018-02), p. 708-725
Abstract:
Benzodiazepines, non‐selective positive allosteric modulators (PAMs) of GABA A receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype‐selective PAMs. Experimental Approach In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits. In vivo receptor occupancy (RO) was conducted, prior to confirmation of in vivo α2/3 and α1 pharmacology through quantitative EEG (qEEG) beta frequency and zolpidem drug discrimination in rats respectively. PF‐06372865 was then progressed to Phase 1 clinical trials. Key Results PF‐06372865 exhibited functional selectivity for those receptors containing α2/3/5 subunits, with significant positive allosteric modulation (90–140%) but negligible activity (≤20%) at GABA A receptors containing α1 subunits. PF‐06372865 exhibited concentration‐dependent occupancy of GABA A receptors in preclinical species. There was an occupancy‐dependent increase in qEEG beta frequency and no generalization to a GABA A α1 cue in the drug‐discrimination assay, clearly demonstrating the lack of modulation at the GABA A receptors containing an α1 subtype. In a Phase 1 single ascending dose study in healthy volunteers, evaluation of the pharmacodynamics of PF‐06372865 demonstrated a robust increase in saccadic peak velocity (a marker of α2/3 pharmacology), increases in beta frequency qEEG and a slight saturating increase in body sway. Conclusions and Implications PF‐06372865 has a unique clinical pharmacology profile and a highly predictive translational data package from preclinical species to the clinical setting.
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2029728-2
SSG:
15,3