2. Academic Validation
  3. Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560)

Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560)

  • J Med Chem. 2023 Nov 21. doi: 10.1021/acs.jmedchem.3c01635.
István Ledneczki 1,  Zsolt Némethy 1,  Katalin Dudásné Molnár 1,  Pál Tapolcsányi 1,  Viktor Ilkei 1,  István Vágó 1,  Sándor Kolok 1,  Márta Thán 1,  Judit Laszy 1,  Ottilia Balázs 1,  Balázs Krámos 1,  Áron Szigetvári 1,  Imre Bata 1,  Attila Makó 1,  András Visegrády 1,  László Fodor 1,  Mónika Vastag 1,  György Lévay 1,  Balázs Lendvai 1,  István Greiner 1,  János Éles 1
Affiliations

Affiliation

  • 1 Gedeon Richter Plc, 19-21 Gyömői útca, Budapest H-1103, Hungary.
PMID: 37989278 DOI: 10.1021/acs.jmedchem.3c01635
Abstract

During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for in vitro activity. With the aim of further improvements, more thorough modifications were also carried out. As a result, a new chemotype (the azetidinespirochromone family) was identified, which proved to be 1 order of magnitude less lipophilic retaining the same high level of in vitro potency as the lead series itself, however, with improved metabolic stability and kinetic solubility. Compound 53 showed the most balanced physicochemical and pharmacological profile with significant in vivo efficacy in the scopolamine-induced amnesia test. Based on these promising results, cognitive enhancement through the positive modulation of α7 nAChRs appears to be a viable approach. Compound 53 was selected to be a preclinical development candidate (as RGH-560).

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