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)...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2003-12, Vol.13 (24), p.4409-4413
Hauptverfasser:	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
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Amines - chemical synthesis Amines - pharmacology Binding Sites Biological Availability Drug Design Humans Indoles - chemical synthesis Indoles - pharmacology Kinetics Molecular Conformation Receptor, Serotonin, 5-HT1B - chemistry Receptor, Serotonin, 5-HT1B - drug effects Receptor, Serotonin, 5-HT1B - physiology Serotonin Receptor Agonists - administration & dosage Serotonin Receptor Agonists - chemical synthesis Serotonin Receptor Agonists - chemistry Serotonin Receptor Agonists - pharmacology Structure-Activity Relationship
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Zusammenfassung:	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%).
ISSN:	0960-894X