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
  • 1. Ryvu Therapeutics S.A., Sternbacha Street 2, 30-394 Kraków, Poland. Electronic address: [email protected].
  • 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.
Products