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

Abstract

BACKGROUND AND PURPOSEActivation of the α7 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 α7-nACh receptor agonist AQW051 as a promising drug candidate for this indication. EXPERIMENTAL APPROACHAQW051 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 RESULTSIn vitro, AQW051 bound with high affinity to α7-nACh receptors and stimulated calcium influx in cells recombinantly expressing the human α7-nACh receptor. 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 two-to threefold accumulation compared with steady state was achieved by 1 week.

Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors

“…In vitro assessment of AQW051 at a7 nAChRs expressed in Xenopus oocytes revealed that this compound displayed an EC 50 of 7.5 mM but acted as a partial agonist, evoking only 75% of the ACh-evoked current. This compound inhibited the 5-HT 3 receptors with an IC 50 of 19 mM, demonstrating a better a7 nAChR/5-HT 3 selectivity profile than RG3487 and encenicline (Feuerbach et al, 2015). This compound also demonstrated a sufficient PK profile, with rapid CNS permeability, and activity in exploration in the rat social recognition model and an improved mouse sensory gating profile (DBA/2).…”

“…Tested in clinical trials in schizophrenia patients, RG3487 showed no significant improvement of the cognitive deficit associated with schizophrenia, but patients with moderate negative symptoms exhibited a significant improvement in their symptoms (Umbricht et al, 2014). Novartis (Basel, Switzerland) also recently disclosed a quinuclidine ether a7 nAChR agonist, AQW051 (Di Paolo et al, 2014;Feuerbach et al, 2015). In vitro assessment of AQW051 at a7 nAChRs expressed in Xenopus oocytes revealed that this compound displayed an EC 50 of 7.5 mM but acted as a partial agonist, evoking only 75% of the ACh-evoked current.…”

“…Similar effects were reported for another selective a7 nAChR agonist, AQW051 (15 mg/kg) (Di Paolo et al, 2014), indicating that this therapeutic strategy can apply to higher mammals and may be beneficial in humans. It remains, however, to be determined whether activating or desensitizing concentrations of a selective a7 nAChR agonist will be required in humans, because ABT-107 was efficacious at activating and desensitizing doses and AQW051 at only desensitizing doses in the MPTP monkey model (Bitner et al, 2010;Feuerbach et al, 2015). If desensitizing concentrations are required, the effects on dyskinesia of a7 nAChR agonists may be achieved at the expense of improvements in cognition.…”

The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

“…In mice, the half-life of AQW051 was *0.8 h, and high brain/plasma ratios of 10-80 at 0.08-7 h were observed [98]. AQW051 was proposed as a potentially useful agent for the treatment of cognitive deficits associated with a variety of disorders, including schizophrenia, and subsequently evaluated in three phase I studies [65,98]. Pharmacokinetics and tolerability of AQW051 were evaluated in three phase I, placebo-controlled studies in 180 healthy subjects [65].…”

“…AQW051 was proposed as a potentially useful agent for the treatment of cognitive deficits associated with a variety of disorders, including schizophrenia, and subsequently evaluated in three phase I studies [65,98]. Pharmacokinetics and tolerability of AQW051 were evaluated in three phase I, placebo-controlled studies in 180 healthy subjects [65]. AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event profile similar to that of placebo, and no serious adverse events were reported at single oral doses up to 200 mg or multiple daily doses up to 75 mg [65].…”