1-Sulfonyl-6-Piperazinyl-7-Azaindoles as potent and pseudo-selective 5-HT6 receptor antagonists.
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 D2 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 D3 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.
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Charles-Henry
CH
Fabritius
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Ullamari
U
Pesonen
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Josef
J
Messinger
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Raymond
R
Horvath
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Harri
H
Salo
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Michał
M
Gałęzowski
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Mariusz
M
Galek
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Klaudia
K
Stefańska
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Joanna
J
Szeremeta-Spisak
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Marta
M
Olszak-Płachta
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Anna
A
Buda
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Justyna
J
Adamczyk
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Marcin
M
Król
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Peteris
P
Prusis
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Magdalena
M
Sieprawska-Lupa
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Maciej
M
Mikulski
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Katja
K
Kuokkanen
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Hugh
H
Chapman
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland.
Radosław
R
Obuchowicz
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Timo
T
Korjamo
Orion Corporation, Orion Pharma, Orionintie 1A, 02200 Espoo, Finland.
Niina
N
Jalava
Selvita S.A., Ul. Bobrzyńskiego 14, 30-348 Krakow, Poland. Electronic address: mateusz.nowak@selvita.com.
Mateusz
M
Nowak
D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012601:Scopolamine; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D007211:Indoles; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor; D012601:Scopolamine
5-HT(6) receptor; Antagonists; Azaindole; Cognitive impairment; Serotonin receptor