Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket.

Autor: van Loevezijn A; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., Venhorst J; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. Electronic address: jennifer.mccormack@tno.nl., Iwema Bakker WI; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., Lange JHM; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., de Looff W; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., Henzen R; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., de Vries J; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., van de Woestijne RP; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., den Hartog AP; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., Verhoog S; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., van der Neut MAW; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., de Bruin NMWJ; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands., Kruse CG; Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Mar 15; Vol. 26 (6), pp. 1605-1611. Date of Electronic Publication: 2016 Feb 02.
DOI: 10.1016/j.bmcl.2016.02.001
Abstrakt: The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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