| Autor: |
van Loevezijn A; Abbott Healthcare Products B.V. (formerly Solvay Pharmaceuticals B.V. ), C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. arnold.vanloevezijn@online.nl, Venhorst J, Iwema Bakker WI, de Korte CG, de Looff W, Verhoog S, van Wees JW, van Hoeve M, van de Woestijne RP, van der Neut MA, Borst AJ, van Dongen MJ, de Bruin NM, Keizer HG, Kruse CG |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2011 Oct 27; Vol. 54 (20), pp. 7030-54. Date of Electronic Publication: 2011 Sep 26. |
| DOI: |
10.1021/jm200466r |
| Abstrakt: |
The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT(6)R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT(6)R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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