2. Academic Validation
  3. 5-HT6 receptor antagonists. Design, synthesis, and structure-activity relationship of substituted 2-(1-methyl-4-piperazinyl)pyridines

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

  • Bioorg Med Chem Lett. 2023 Oct 6:96:129497. doi: 10.1016/j.bmcl.2023.129497.
Michał Gałęzowski 1,  Charles-Henry Fabritius 2,  Ullamari Pesonen 3,  Harri Salo 3,  Marta Olszak-Płachta 2,  Klaudia Czerwińska 2,  Justyna Adamczyk 2,  Marcin Król 2,  Peteris Prusis 3,  Magdalena Sieprawska-Lupa 2,  Maciej Mikulski 2,  Katja Kuokkanen 3,  Radosław Obuchowicz 2,  Timo Korjamo 3,  Niina Jalava 3,  Agnieszka Nikiforuk 4,  Mateusz Nowak 2
Affiliations

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.

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