title: Design, synthesis and biological activity of novel dimethyl-[2-[6-substituted-indol-1-yl]-ethyl]-amine as potent, selective, and orally-bioavailable 5-HT(1D) agonists.
abstract: 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%).
authors.affiliation: NPS Pharmaceuticals Inc., 6850 Goreway Drive, Mississauga, ON, Canada L4V 1V7. misaac@npsp.com
authors.forename: Methvin
authors.initials: M
authors.lastname: Isaac
authors.forename: Malik
authors.initials: M
authors.lastname: Slassi
authors.forename: Tao
authors.initials: T
authors.lastname: Xin
authors.forename: Jalaj
authors.initials: J
authors.lastname: Arora
authors.forename: Anne
authors.initials: A
authors.lastname: O'Brien
authors.forename: Louise
authors.initials: L
authors.lastname: Edwards
authors.forename: Neil
authors.initials: N
authors.lastname: MacLean
authors.forename: Julie
authors.initials: J
authors.lastname: Wilson
authors.forename: Lidia
authors.initials: L
authors.lastname: Demschyshyn
authors.forename: Phillipe
authors.initials: P
authors.lastname: Labrie
authors.forename: Angela
authors.initials: A
authors.lastname: Naismith
authors.forename: Shawn
authors.initials: S
authors.lastname: Maddaford
authors.forename: Damon
authors.initials: D
authors.lastname: Papac
authors.forename: Shuree
authors.initials: S
authors.lastname: Harrison
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Stan
authors.initials: S
authors.lastname: Draper
authors.forename: Ashok
authors.initials: A
authors.lastname: Tehim
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D001682:Biological Availability; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008968:Molecular Conformation; D044302:Receptor, Serotonin, 5-HT1B / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D007211:Indoles; D044302:Receptor, Serotonin, 5-HT1B; D017366:Serotonin Receptor Agonists