Design and Synthesis of Novel Deuterated Ligands Functionally Selective for the γ-Aminobutyric Acid Type A Receptor (GABAA R) α6 Subtype with Improved Metabolic Stability and Enhanced Bioavailability

Journal of Medicinal Chemistry
Daniel E KnutsonJames M Cook

Abstract

Recent reports indicate that α6β2/3γ2 GABAAR selective ligands may be important for the treatment of trigeminal activation-related pain and neuropsychiatric disorders with sensori-motor gating deficits. Based on 3 functionally α6β2/3γ2 GABAAR selective pyrazoloquinolinones, 42 novel analogs were synthesized, and their in vitro metabolic stability and cytotoxicity as well as their in vivo pharmacokinetics, basic behavioral pharmacology, and effects on locomotion were investigated. Incorporation of deuterium into the methoxy substituents of the ligands increased their duration of action via improved metabolic stability and bioavailability, while their selectivity for the GABAAR α6 subtype was retained. 8b was identified as the lead compound with a substantially improved pharmacokinetic profile. The ligands allosterically modulated diazepam insensitive α6β2/3γ2 GABAARs and were functionally silent at diazepam sensitive α1β2/3γ2 GABAARs, thus no sedation was detected. In addition, these analogs were not cytotoxic, which render them interesting candidates for treatment of CNS disorders mediated by GABAAR α6β2/3γ2 subtypes.

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Citations

Mar 24, 2020·Expert Opinion on Therapeutic Patents·Letizia Crocetti, Gabriella Guerrini
Mar 25, 2019·International Journal of Molecular Sciences·Gabriella GuerriniLetizia Crocetti
Jan 13, 2021·Journal of Cheminformatics·A Patrícia BentoAndrew R Leach
Oct 29, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Hung-Ruei TzengLih-Chu Chiou
Jun 23, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jelena R MitrovićSnežana D Savić
Mar 17, 2021·European Journal of Pharmacology·Milica Gajić BojićMiroslav M Savić
Mar 17, 2021·The Journal of Organic Chemistry·Michael A Schmidt
Aug 24, 2019·Organic Letters·Ming-Hui ZhuWen-Bo Liu
Jan 15, 2019·Journal of Medicinal Chemistry·Tracey PiraliArmando A Genazzani

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