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.
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%).
Isaac
Methvin
M
NPS Pharmaceuticals Inc., 6850 Goreway Drive, Mississauga, ON, Canada L4V 1V7. misaac@npsp.com
Slassi
Malik
M
Xin
Tao
T
Arora
Jalaj
J
O'Brien
Anne
A
Edwards
Louise
L
MacLean
Neil
N
Wilson
Julie
J
Demschyshyn
Lidia
L
Labrie
Phillipe
P
Naismith
Angela
A
Maddaford
Shawn
S
Papac
Damon
D
Harrison
Shuree
S
Wang
Hua
H
Draper
Stan
S
Tehim
Ashok
A
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
D000588:Amines; D007211:Indoles; D044302:Receptor, Serotonin, 5-HT1B; D017366:Serotonin Receptor Agonists