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AQW051, a novel, potent and selective nicotinic acetylcholine receptor α7 partial agonist: Pharmacological characterisation and Phase I evaluation in healthy subjects

Feuerbach, Dominik and Pezous, Nicole and Weiss, Markus and Shakeri-Nejad, Kasra and Lingenhoehl, Kurt and Hoyer, Daniel and Hurth, Konstanze and Bilbe, Graeme and Pryce, Christopher R and Mcallister, Kevin and Chaperon, Frederique and Kucher, Klaus and Johns, Donald and Blaettler, Thomas and Lopez Lopez, Cristina (2014) AQW051, a novel, potent and selective nicotinic acetylcholine receptor α7 partial agonist: Pharmacological characterisation and Phase I evaluation in healthy subjects. Journal pharmacology and experimental therapeutics.

Abstract

Activation of the nicotinic acetylcholine receptor (nAChR) α7 is considered as an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel nAChR α7 agonist AQW051 as a promising drug candidate for this indication. In vitro, AQW051 bound with very high affinity to nAChR α7 and displayed considerably lower potency for other human nAChRs subtypes including α4β2, α3β4 and α1β1γδ receptors, as well as 5 HT3 receptors when tested functionally as an antagonist. Furthermore, AQW051 did not display agonistic activity at these other receptors. Similarly, AQW051 showed low binding activity at a wide panel of neurotransmitter receptors, transporters and kinases. Demonstrating that AQW051 is a potent, partial and selective agonist of nAChR α7. 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 experiment in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly volunteers, with an adverse event (AE) profile comparable with placebo. No serious adverse events (SAEs) were reported and all AEs were either mild or moderate in severity. Once daily oral administration of AQW051 resulted in continuous exposure and a 2-3 fold accumulation compared with steady state was achieved by one week; exposure was not affected by a light meal. Taken together, these data support further development of AQW051 as a cognitive-enhancing agent.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/21412

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