2. Academic Validation
  3. Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABAA Receptor Negative Allosteric Modulators

Multiparameter Optimization of Naphthyridine Derivatives as Selective α5-GABAA Receptor Negative Allosteric Modulators

  • J Med Chem. 2022 Jun 9;65(11):7876-7895. doi: 10.1021/acs.jmedchem.2c00414.
György Szabó 1,  Olivér Éliás 1,  Péter Erdélyi 1,  Attila Potor 1,  György I Túrós 1,  Benedek I Károlyi 1,  Gábor Varró 1,  Ágnes Gy Vaskó 1,  Imre Bata 1,  Gábor L Kapus 1,  Zoltán Dohányos 1,  Amrita Á Bobok 1,  László Fodor 1,  Márta Thán 1,  Mónika Vastag 1,  Zsolt Komlódi 1,  Rita É Soukupné Kedves 1,  Éva Makó 1,  Brigitta Süveges 1,  István Greiner 1
Affiliations

Affiliation

  • 1 Gedeon Richter Plc., 19-21. Gyömrői út, Budapest, 1103 Hungary.
PMID: 35584373 DOI: 10.1021/acs.jmedchem.2c00414
Abstract

The discovery and characterization of novel naphthyridine derivatives with selective α5-GABAAR negative allosteric modulator (NAM) activity are disclosed. Utilizing a scaffold-hopping strategy, fused [6 + 6] bicyclic scaffolds were designed and synthesized. Among these, 1,6-naphthyridinones were identified as potent and selective α5-GABAAR NAMs with metabolic stability, cardiac safety, and beneficial intellectual property (IP) issues. Relocation of the oxo acceptor function and subsequent modulation of the physicochemical properties resulted in novel 1,6-naphthyridines with improved profile, combining good potency, selectivity, ADME, and safety properties. Besides this, compound 20, having the most balanced profile, provided in vivo proof of concept (POC) for the new scaffold in two animal models of cognitive impairment associated with schizophrenia (CIAS).

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