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AQW 051, a novel, potent and selective α 7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation
Author(s) -
Feuerbach Dominik,
Pezous Nicole,
Weiss Markus,
ShakeriNejad 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
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13001
Subject(s) - partial agonist , agonist , tolerability , pharmacology , placebo , pharmacokinetics , nicotinic agonist , medicine , oral administration , receptor , adverse effect , pathology , alternative medicine
Background and Purpose Activation of the α 7 nicotinic ACh receptor ( nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α 7‐ nACh receptor agonist AQW 051 as a promising drug candidate for this indication. Experimental Approach AQW 051 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 , AQW 051 bound with high affinity to α 7‐ nACh receptors and stimulated calcium influx in cells recombinantly expressing the human α 7‐ nACh receptor . In vivo , AQW 051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW 051 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, AQW 051 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 AQW 051 resulted in continuous exposure and a two‐ to threefold accumulation compared with steady state was achieved by 1 week. Conclusions and Implications These data support further development of AQW 051 as a cognitive‐enhancing agent, as a therapeutic, for example, in A lzheimer's disease or schizophrenia.