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Pharmacology in translation: the preclinical and early clinical profile of the novel ?2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865.

ABSTRACT: BACKGROUND AND PURPOSE:Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the ?1 subunit, there has been a concerted effort to develop ?2/3 subtype-selective PAMs. EXPERIMENTAL APPROACH:In vitro screening assays were used to identify molecules with functional selectivity for receptors containing ?2/3 subunits over those containing ?1 subunits. In vivo receptor occupancy (RO) was conducted, prior to confirmation of in vivo ?2/3 and ?1 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 ?2/3/5 subunits, with significant positive allosteric modulation (90-140%) but negligible activity (?20%) at GABAA receptors containing ?1 subunits. PF-06372865 exhibited concentration-dependent occupancy of GABAA receptors in preclinical species. There was an occupancy-dependent increase in qEEG beta frequency and no generalization to a GABAA ?1 cue in the drug-discrimination assay, clearly demonstrating the lack of modulation at the GABAA receptors containing an ?1 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 ?2/3 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.

SUBMITTER: Nickolls SA

PROVIDER: S-EPMC5786456 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA<sub>A</sub> receptor positive allosteric modulator PF-06372865.

Nickolls Sarah A SA Gurrell Rachel R van Amerongen Guido G Kammonen Juha J Cao Lishuang L Brown Adam R AR Stead Clara C Mead Andy A Watson Christine C Hsu Cathleen C Owen Robert M RM Pike Andy A Fish Rebecca L RL Chen Laigao L Qiu Ruolun R Morris Evan D ED Feng Gang G Whitlock Mark M Gorman Donal D van Gerven Joop J Reynolds David S DS Dua Pinky P Butt Richard P RP

British journal of pharmacology 20180118 4

<h4>Background and purpose</h4>Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABA<sub>A</sub> 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.<h4>Experimental approach</h4>In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those con ...[more]

PMID: 29214652

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Project description:Introduction: Dravet syndrome (DS) is an intractable epilepsy syndrome concomitant with neurodevelopmental disorder that begins in infancy. DS is dominantly caused by mutations in the SCN1A gene, which encodes the α subunit of a voltage-gated Na channel. Pre-synaptic inhibitory dysfunction is regarded as the pathophysiological mechanism, but an effective strategy for ameliorating seizures and behavioral problems is still under development. Here, we evaluated the effects of KRM-II-81, a newly developed positive allosteric modulator for α 2/3 subunit containing GABAA receptors (α2/3-GABAAR) in a mice model of DS both in vivo and at the neuronal level. Methods: We used knock-in mice carrying a heterozygous, clinically relevant SCN1A mutation (background strain: C57BL/6 J) as a model of the DS (Scn1a WT/A1783V mice), knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V). Seizure threshold and locomotor activity was evaluated by using the hyperthermia-induced seizure paradigm and open filed test, respectively. Anxiety-like behavior was assessed by avoidance of the center region in locomotor activity. We estimated a sedative effect by the total distance traveled in locomotor activity and grip strength. Inhibitory post synaptic currents (IPSCs) were recorded from a hippocampal CA1 pyramidal neuron in an acutely prepared brain slice. Results: KRM-II-81 significantly increased the seizure threshold of Scn1a WT/A1783V mice in a dose-dependent manner. A low dose of KRM-II-81 specifically improved anxiety-like behavior of Scn1a WT/A1783V mice. A sedative effect was induced by relatively high dose of KRM-II-81 in Scn1a WT/A1783V mice, the dose of which was not sedative for WT mice. KRM-II-81 potentiated IPSCs by increasing its decay time kinetics. This effect was more prominent in Scn1a WT/A1783V mice. Discussion: Higher activation of α2/3-GABAAR by KRM-II-81 suggests a compensatory modification of post synaptic inhibitory function against presynaptic inhibitory dysfunction in Scn1a WT/A1783V. The increased sensitivity for KRM-II-81 may be relevant to the distinct dose-dependent effect in each paradigm of Scn1a WT/A1783V mice. Conclusion: Selective activation for α2/3-GABAAR by KRM-II-81 could be potential therapeutic strategy for treating seizures and behavioral problems in DS.

Project description:The amyloid-β peptide (Aβ)-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aβ synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

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Dataset Information

Pharmacology in translation: the preclinical and early clinical profile of the novel ?2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865.

Publications

Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA<sub>A</sub> receptor positive allosteric modulator PF-06372865.

Similar Datasets

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