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  3. Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

  • Sci Rep. 2021 Apr 8;11(1):7700. doi: 10.1038/s41598-021-87307-7.
Joerg F Hipp 1,  Frederic Knoflach 1,  Robert Comley 1 2,  Theresa M Ballard 1 3,  Michael Honer 1,  Gerhard Trube 1,  Rodolfo Gasser 4,  Eric Prinssen 1,  Tanya L Wallace 5 6,  Andreas Rothfuss 4,  Henner Knust 7,  Sian Lennon-Chrimes 8,  Michael Derks 8,  Darren Bentley 8,  Lisa Squassante 1,  Stephane Nave 1,  Jana Nöldeke 1,  Christoph Wandel 4,  Andrew W Thomas 7 9,  Maria-Clemencia Hernandez 10
Affiliations

Affiliations

  • 1 Neuroscience & Rare Diseases (NRD) Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • 2 AbbVie Inc, North Chicago, IL, USA.
  • 3 Galwyn (UK) Ltd, Dartmouth, Devon, UK.
  • 4 Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • 5 CNS Research, Roche Bioscience, Palo Alto, USA.
  • 6 BlackThorn Therapeutics, 780 Brannan Street, San Francisco, CA, 94103, USA.
  • 7 Small Molecule Research, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • 8 Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Welwyn, Welwyn Garden City, AL7 1TW, UK.
  • 9 Helvetica Capital AG, Zurich, Switzerland.
  • 10 Neuroscience & Rare Diseases (NRD) Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. maria-clemencia.hernandez@roche.com.
PMID: 33833333 DOI: 10.1038/s41598-021-87307-7
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.

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