A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
1-Sulfonyl-6-Piperazinyl-7-Azaindoles as potent and pseudo-selective 5-HT6 receptor antagonists
Tekijät: Fabritius CH, Pesonen U, Messinger J, Horvath R, Salo H, Galezowski M, Galek M, Stefanska K, Szeremeta-Spisak J, Olszak-Plachta M, Buda A, Adamczyk J, Krol M, Prusis P, Sieprawska-Lupa M, Mikulski M, Kuokkanen K, Chapman H, Obuchowicz R, Korjamo T, Jalava N, Nowak M
Kustantaja: PERGAMON-ELSEVIER SCIENCE LTD
Julkaisuvuosi: 2016
Journal: Bioorganic and Medicinal Chemistry Letters
Tietokannassa oleva lehden nimi: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Lehden akronyymi: BIOORG MED CHEM LETT
Vuosikerta: 26
Numero: 11
Aloitussivu: 2610
Lopetussivu: 2615
Sivujen määrä: 6
ISSN: 0960-894X
DOI: https://doi.org/10.1016/j.bmcl.2016.04.024
A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D-2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D-3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists. (C) 2016 Elsevier Ltd. All rights reserved.
