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

• Published in: Journal of medicinal chemistry Vol. 66; no. 23; pp. 16276 - 16302
• Main Authors: Ledneczki, István, Némethy, Zsolt, Molnár, Katalin Dudásné, Tapolcsányi, Pál, Ilkei, Viktor, Vágó, István, Kolok, Sándor, Thán, Márta, Laszy, Judit, Balázs, Ottilia, Krámos, Balázs, Szigetvári, Áron, Bata, Imre, Makó, Attila, Visegrády, András, Fodor, László, Vastag, Mónika, Lévay, György, Lendvai, Balázs, Greiner, István, Éles, János
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.12.2023; Amer Chemical Soc
• Subjects: Allosteric Regulation; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Chemistry, Medicinal; Indoles - pharmacology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Receptors, Nicotinic - metabolism; Science & Technology; ACTIVATION; TRANSMISSION; PROFILES; METAANALYSIS; ACCURATE DOCKING; SCHIZOPHRENIA; RECOGNITION MEMORY; DIVERSITY; SMOKING; BINDING
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01635

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).