Novel imidazo[1,5-a]quinoxaline derivatives: SAR, selectivity and modeling challenges en route to the identification of an α5-GABAA receptor NAM

Benedek Imre Károlyi; Attila Potor; Gábor László Kapus; László Fodor; Amrita Bobok; Balázs Krámos; Ildikó Magdó; Imre Bata; György Szabó

doi:10.1016/j.bmcl.2022.129107

Novel imidazo[1,5-a]quinoxaline derivatives: SAR, selectivity and modeling challenges en route to the identification of an α5-GABAA receptor NAM

Bioorg Med Chem Lett. 2023 Jan 15:80:129107. doi: 10.1016/j.bmcl.2022.129107. Epub 2022 Dec 19.

Authors

Benedek Imre Károlyi¹, Attila Potor², Gábor László Kapus², László Fodor², Amrita Bobok², Balázs Krámos², Ildikó Magdó², Imre Bata², György Szabó²

Affiliations

¹ Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary. Electronic address: karolyibi@richter.hu.
² Gedeon Richter Plc, Budapest 10, PO Box 27, H-1475, Hungary.

PMID: 36549396
DOI: 10.1016/j.bmcl.2022.129107

Abstract

Initial optimization of a series of novel imidazo[1,5-a]quinoxaline compounds originated from a heuristic approach combining two known structural moieties towards α5-GABA_A receptor is shown. This work reveals one-digit nanomolar active compounds as well as positive and negative allosteric modulators resulted from our exploratory approach. To deepen our understanding, their diverse mechanistic nature resulted from in silico modeling is also disclosed.

Keywords: Displacement; Imidazo[1,5-a]quinoxaline; Modelling; Patch clamp; SAR; Selectivity; α5-GABA(A) modulator.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Quinoxalines* / pharmacology
Receptors, GABA-A*

Substances

Receptors, GABA-A
Quinoxalines