Design, Synthesis, and
Pharmacological Evaluation
of Piperidin-4-yl amino aryl sulfonamides: Novel, Potent, Selective,
Orally Active, and Brain Penetrant 5‑HT<sub>6</sub> Receptor
Antagonists
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Abstract
Our initial findings around aryl sulfonamide series led
to <i>N</i>-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy
benzenesulfonamide as potent and selective 5-HT<sub>6</sub> receptor
(5-HT<sub>6</sub>R) antagonist with reasonable pharmacokinetic properties
and activity in animal models of cognition. However, lack of brain
penetration and P-glycoprotein liability makes this scaffold unsuitable
for further development. Our goal was to identify small molecule 5-HT<sub>6</sub>R antagonist with adequate brain penetration, acceptable ADME
properties, no P-glycoprotein, and no hERG liability. Several structural
modifications including bringing conformational constraint around
the sulfonamide −NH group and introduction of a heteroatom
to modulate the physicochemical properties were attempted. This effort
culminated in the discovery of series of novel, potent, selective,
orally bioavailable, and adequately brain penetrant compounds with
no hERG liability. These compounds showed activity in animal models
of cognition like object recognition task and water maze and in brain
microdialysis studies at lower doses