A series
of chemical optimizations guided by in vitro affinity
at a histamine H3 receptor (H3R), physicochemical
properties, and pharmacokinetics in rats resulted in identification
of N-[4-(1-cyclobutyl-piperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide
dihydrochloride (17v, SUVN-G3031) as a clinical candidate.
Compound 17v is a potent (hH3R K
i = 8.73 nM) inverse agonist at H3R with selectivity
over other 70 targets, Compound 17v has adequate oral
exposures and favorable elimination half-lives both in rats and dogs.
It demonstrated high receptor occupancy and marked wake-promoting
effects with decreased rapid-eye-movement sleep in orexin-B saporin
lesioned rats supporting its potential therapeutic utility in treating
human sleep disorders. It had no effect on the locomotor activity
at doses several fold higher than its efficacious dose. It is devoid
of hERG and phospholipidosis issues. Phase-1 evaluation for safety,
tolerability, and pharmacokinetics, and long-term safety studies in
animals have been successfully completed without any concern for further
development.
In continuation to our efforts to develop better treatment options for cognitive decline, we have been focussing on 5-HT 6 receptor (5-HT 6 R) antagonists, which are known to be involved in improving cognitive function in numerous animal models. In this paper, we report a novel series of [3-[(1-Methylpiperidin-4-yl) methyl] arylsulfonyl]-1H-indole derivatives as potent and selective 5-HT 6 R antagonists. The lead compound from this series shows potent in vitro binding affinity, functional antagonistic activity at 5-HT 6 R, good pharmacokinetic profile, excellent selectivity and no Cytochrome P450 liabilities.
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