Isaac Methvin, Slassi Malik, Xin Tao, Arora Jalaj, O'Brien Anne, Edwards Louise, MacLean Neil, Wilson Julie, Demschyshyn Lidia, Labrie Phillipe, Naismith Angela, Maddaford Shawn, Papac Damon, Harrison Shuree, Wang Hua, Draper Stan, Tehim Ashok
NPS Pharmaceuticals Inc., 6850 Goreway Drive, Mississauga, ON, Canada L4V 1V7.
Bioorg Med Chem Lett. 2003 Dec 15;13(24):4409-13. doi: 10.1016/j.bmcl.2003.09.025.
A novel series of highly potent human 5-HT(1D) 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 (K(i)=2.4 nM) agonist at the human 5-HT(1D) 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 (F(po)=51%).
合成了一系列新型的高效人5-羟色胺（5-HT）(1D)激动剂，即二甲基-[2-[6-取代-吲哚-1-基]-乙基]-胺。构效关系（SAR）研究表明，4-[1-(2-二甲基氨基-乙基)-1H-吲哚-6-基]-四氢-硫代吡喃-4-醇（11b，ALX-2732）是一种强效的（K(i)=2.4 nM）人5-HT(1D)受体激动剂，对其他血清素受体亚型具有良好的选择性。该化合物在人和大鼠肝微粒体中表现出良好的体外代谢稳定性，并且在大鼠中具有口服生物利用度（F(po)=51%）。
