Header

UZH-Logo

Maintenance Infos

AQW051, a novel, potent and selective α7 nicotinic acetylcholine receptor partial agonist: Pharmacological characterization and phase I evaluation


Feuerbach, Dominik; Pezous, Nicole; Weiss, Markus; Shakeri-Nejad, Kasra; Lingenhoehl, Kurt; Hoyer, Daniel; Hurth, Konstanze; Bilbe, Graeme; Pryce, Christopher R; McAllister, Kevin; Chaperon, Frederique; Kucher, Klaus; Johns, Donald; Blaettler, Thomas; Lopez Lopez, Cristina (2015). AQW051, a novel, potent and selective α7 nicotinic acetylcholine receptor partial agonist: Pharmacological characterization and phase I evaluation. British Journal of Pharmacology, 172(5):1292-1304.

Abstract

BACKGROUND AND PURPOSE: Activation of the α7 nicotinic acetylcholine receptor (nAChR) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7-nAChR agonist AQW051 as a promising drug candidate for this indication.
EXPERIMENTAL APPROACH: AQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects.
KEY RESULTS: In vitro, AQW051 bound with high affinity to α7-nAChR and stimulated calcium influx in cells recombinantly expressing the human α7-nAChR. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200 mg and multiple daily doses up to 75 mg. Once-daily oral administration of AQW051 resulted in continuous exposure and a 2-3-fold accumulation compared with steady state was achieved by 1 week.
CONCLUSIONS AND IMPLICATIONS: These data support further development of AQW051 as a cognitive-enhancing agent, for example in Alzheimer's disease or schizophrenia.

Abstract

BACKGROUND AND PURPOSE: Activation of the α7 nicotinic acetylcholine receptor (nAChR) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7-nAChR agonist AQW051 as a promising drug candidate for this indication.
EXPERIMENTAL APPROACH: AQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects.
KEY RESULTS: In vitro, AQW051 bound with high affinity to α7-nAChR and stimulated calcium influx in cells recombinantly expressing the human α7-nAChR. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200 mg and multiple daily doses up to 75 mg. Once-daily oral administration of AQW051 resulted in continuous exposure and a 2-3-fold accumulation compared with steady state was achieved by 1 week.
CONCLUSIONS AND IMPLICATIONS: These data support further development of AQW051 as a cognitive-enhancing agent, for example in Alzheimer's disease or schizophrenia.

Statistics

Citations

10 citations in Web of Science®
11 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Psychiatric University Hospital Zurich > Clinic for Psychiatry, Psychotherapy, and Psychosomatics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2015
Deposited On:16 Jan 2015 14:17
Last Modified:05 Apr 2016 18:49
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0007-1188
Publisher DOI:https://doi.org/10.1111/bph.13001
PubMed ID:25363835

Download

Full text not available from this repository.
View at publisher