Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease.

Abstract

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.

• Authors: Daniel J Buzard, Sangdon Han, Luis Lopez, Andrew Kawasaki, Jeanne Moody, Lars Thoresen, Brett Ullman, Juerg Lehmann, Imelda Calderon, Xiuwen Zhu, Tawfik Gharbaoui, Dipanjan Sengupta, Ashwin Krishnan, Yinghong Gao, Jeff Edwards, Jeremy Barden, Michael Morgan, Khawja Usmani, Chuan Chen, Abu Sadeque, Jayant Thatte, Michelle Solomon, Lixia Fu, Kevin Whelan, Ling Liu, Hussien Al-Shamma, Joel Gatlin, Minh Le, Charles Xing, Sheryll Espinola, Robert M Jones
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 13 Pg. 4404-9 (Jul 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22633692 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Immunologic Factors
• Indoles
• Receptors, Lysosphingolipid

Topics

• Animals
• Autoimmune Diseases (drug therapy)
• Disease Models, Animal
• Female
• Humans
• Immunologic Factors (chemistry, pharmacokinetics, therapeutic use)
• Indoles (chemistry, pharmacokinetics, therapeutic use)
• Lymphocytes (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Microsomes (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Lysosphingolipid (agonists, metabolism)
• Structure-Activity Relationship