5-HT6 receptor antagonists. Design, synthesis, and structure-activity relationship of substituted 2-(1-methyl-4-piperazinyl)pyridines

Michał Gałęzowski; Charles-Henry Fabritius; Ullamari Pesonen; Harri Salo; Marta Olszak-Płachta; Klaudia Czerwińska; Justyna Adamczyk; Marcin Król; Peteris Prusis; Magdalena Sieprawska-Lupa; Maciej Mikulski; Katja Kuokkanen; Radosław Obuchowicz; Timo Korjamo; Niina Jalava; Agnieszka Nikiforuk; Mateusz Nowak

doi:10.1016/j.bmcl.2023.129497

5-HT₆ receptor antagonists. Design, synthesis, and structure-activity relationship of substituted 2-(1-methyl-4-piperazinyl)pyridines

Bioorg Med Chem Lett. 2023 Nov 15:96:129497. doi: 10.1016/j.bmcl.2023.129497. Epub 2023 Oct 6.

Authors

Michał Gałęzowski¹, Charles-Henry Fabritius², Ullamari Pesonen³, Harri Salo³, Marta Olszak-Płachta², Klaudia Czerwińska², Justyna Adamczyk², Marcin Król², Peteris Prusis³, Magdalena Sieprawska-Lupa², Maciej Mikulski², Katja Kuokkanen³, Radosław Obuchowicz², Timo Korjamo³, Niina Jalava³, Agnieszka Nikiforuk⁴, Mateusz Nowak²

Affiliations

¹ Ryvu Therapeutics S.A., Sternbacha Street 2, 30-394 Kraków, Poland. Electronic address: michal.galezowski@ryvu.com.
² Ryvu Therapeutics S.A., Sternbacha Street 2, 30-394 Kraków, Poland.
³ Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
⁴ Department of Behavioral Neuroscience and Drug Development, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.

PMID: 37806499
DOI: 10.1016/j.bmcl.2023.129497

Abstract

In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT₆ receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure-activity relationship (SAR) of these compounds. Our main objective is to improve their activity and selectivity against off-target receptors. Overall, our findings contribute to the advancement of novel compounds targeting the 5-HT₆ receptor. Compound 29 exhibits significant promise in terms of pharmacological, physicochemical, and ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Consequently, it merits thorough exploration as a potential drug candidate due to its favorable activity profile and successful outcomes in a range of in vivo experiments.

Keywords: 5-HT(6) receptor; Antagonists; Non-sulfonyl compounds; Pyridine core; Serotonin receptor.

MeSH terms

Pyridines* / chemistry
Serotonin Antagonists* / chemistry
Structure-Activity Relationship

Substances

serotonin 6 receptor
Pyridines
VP1-001
Serotonin Antagonists