Title of article :
Design, synthesis and biological activity of novel dimethyl-{2-[6-substituted-indol-1-yl]-ethyl}-amine as potent, selective, and orally-Bioavailable 5-HT1D agonists
Author/Authors :
Methvin Isaac، نويسنده , , Malik Slassi، نويسنده , , Tao Xin، نويسنده , , Jalaj Arora، نويسنده , , Anne OʹBrien، نويسنده , , Louise Edwards، نويسنده , , Neil MacLean، نويسنده , , Julie Wilson، نويسنده , , Lidia Demschyshyn، نويسنده , , Phillipe Labrie، نويسنده , , Angela Naismith، نويسنده , , Shawn Maddaford، نويسنده , , Damon Papac، نويسنده , , Shuree Harrison، نويسنده , , Hua Wang، نويسنده , , Stan Draper، نويسنده , , Ashok Tehim، نويسنده ,
Abstract :
A novel series of highly potent human 5-HT1D agonists, dimethyl-{2-[6-substituted-indol-1-yl]-ethyl}-amine, was synthesized. Structure–activity relationship (SAR) investigation revealed 4-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-tetrahydro-thiopyran-4-ol, 11b (ALX-2732), as a potent (Ki=2.4 nM) agonist at the human 5-HT1D receptor with good selectivity over the other serotonin receptor subtypes. This compound demonstrated favorable in vitro metabolic stability in human and rat liver microsomes and was found to be orally bioavailable in rats (Fpo=51%).
