Abstract
GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.
Highlights
Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland. 3Small Molecule Research, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland. 4Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Welwyn, Welwyn Garden City AL7 1TW, UK. 5CNS Research, Roche Bioscience, Palo Alto, USA. 6Present address: AbbVie Inc, North Chicago, IL, USA. 7Present address: Galwyn (UK) Ltd, Dartmouth, Devon, UK. 8Present address: BlackThorn Therapeutics, 780 Brannan Street, San Francisco, CA 94103, USA. 9Present address: Helvetica Capital
Further preclinical studies suggest that G ABAA-α5 negative allosteric modulator (NAM) may attenuate cognitive impairment associated with Down syndrome (DS)[17,18], cognitive impairment associated with schizophrenia (CIAS) as shown by improvements in preclinical models of NMDA dysfunction[19,20,21] and cognitive impairment after anesthesia[22]
Basmisanil was discovered in a medicinal chemistry effort starting from the results of a 56,265 small molecular-weight compound library high-throughput screen based on [3H]-flumazenil competition-binding followed by electrophysiological experiments on cloned GABAA receptor subtypes to determine the functional activity of the initial hits
Summary
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland. 3Small Molecule Research, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland. 4Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Welwyn, Welwyn Garden City AL7 1TW, UK. 5CNS Research, Roche Bioscience, Palo Alto, USA. 6Present address: AbbVie Inc, North Chicago, IL, USA. 7Present address: Galwyn (UK) Ltd, Dartmouth, Devon, UK. 8Present address: BlackThorn Therapeutics, 780 Brannan Street, San Francisco, CA 94103, USA. 9Present address: Helvetica Capital. Nonselective GABAA receptor NAMs have so far only been tested in experiments on animal behavior and in very few exploratory human studies They showed cognition enhancing properties; further clinical development of these non-selective compounds was prevented by anxiogenic or proconvulsive side e ffects[4,5,6,7,8,9]. Both genetic and pharmacological studies have demonstrated that GABAA-α5 subunit-containing receptors play an important modulatory role in learning and memory processes, in line with their preferential expression in the hippocampus and cortical regions[10]. Basmisanil was discovered in a medicinal chemistry effort starting from the results of a 56,265 small molecular-weight compound library high-throughput screen based on [3H]-flumazenil competition-binding followed by electrophysiological experiments on cloned GABAA receptor subtypes to determine the functional activity of the initial hits
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