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

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 furthe...

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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
Online Access	Get full text
ISSN	0022-2623 1520-4804 1520-4804
DOI	10.1021/acs.jmedchem.3c01635

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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).
AbstractList	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 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 potency as the lead series itself, however, with improved metabolic stability and kinetic solubility. Compound showed the most balanced physicochemical and pharmacological profile with significant 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 was selected to be a preclinical development candidate (as ). 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 alpha 7 nAChRs appears to be a viable approach. Compound 53 was selected to be a preclinical development candidate (as RGH-560). 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).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). 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).
Author	Vastag, Mónika Kolok, Sándor Krámos, Balázs Éles, János Lévay, György Visegrády, András Bata, Imre Thán, Márta Makó, Attila Némethy, Zsolt Ledneczki, István Greiner, István Szigetvári, Áron Lendvai, Balázs Vágó, István Laszy, Judit Fodor, László Molnár, Katalin Dudásné Ilkei, Viktor Balázs, Ottilia Tapolcsányi, Pál
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SubjectTerms	Allosteric Regulation alpha7 Nicotinic Acetylcholine Receptor - metabolism Chemistry, Medicinal Indoles - pharmacology Life Sciences & Biomedicine Pharmacology & Pharmacy Receptors, Nicotinic - metabolism Science & Technology
Title	Optimization of Novel α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators and the Discovery of a Preclinical Development Candidate Molecule (RGH-560)
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