The chemical evolution of N,N-dimethyl-2-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]ethylamine (L-741,604) and analogues: Potent and selective agonists for 5-HT 1D receptors

• Published in: Bioorganic & medicinal chemistry letters Vol. 6; no. 15; pp. 1825 - 1830
• Main Authors: Sternfeld, Francine, Baker, Raymond, Broughton, Howard B., Guiblin, Alexander R., Jelley, Richard A., Matassa, Victor G., Reeve, Austin J., Beer, Margaret S., Stanton, Josephine A., Hargreaves, Richard J., Shepheard, Sara L., Longmore, Jeanette, Razzaque, Zerin, Graham, Michael I., Sohal, Bindi, Street, Leslie J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 1996
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/0960-894X(96)00324-1

Optimisation of a series of 5-(heterocyclyl)tryptamines led to the identification of the symmetrically substituted, N-4 linked 1,2,4-triazole as the best indole C-5 substituent for 5-HT 1D receptor affinity and selectivity. The triazole ( 8) is the most potent and selective, orally bioavailable, 5-HT 1D receptor agonist identified to date, showing an order of magnitude greater potency than the clinical compound sumatriptan with improved subtype selectivity. In a series of 5-(heterocyclyl)tryptamines, the symmetrically substituted, N-4 linked 1,2,4-triazole was identified as the best indole C-5 substituent for 5-HT 1D receptor affinity and selectivity. The triazole ( 8) is the most potent and selective, orally bioavailable, 5-HT 1D receptor agonist identified to date.