1. Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease.
- Author
-
Buzard DJ, Han S, Lopez L, Kawasaki A, Moody J, Thoresen L, Ullman B, Lehmann J, Calderon I, Zhu X, Gharbaoui T, Sengupta D, Krishnan A, Gao Y, Edwards J, Barden J, Morgan M, Usmani K, Chen C, Sadeque A, Thatte J, Solomon M, Fu L, Whelan K, Liu L, Al-Shamma H, Gatlin J, Le M, Xing C, Espinola S, and Jones RM
- Subjects
- Animals, Autoimmune Diseases drug therapy, Disease Models, Animal, Female, Humans, Immunologic Factors pharmacokinetics, Immunologic Factors therapeutic use, Indoles pharmacokinetics, Indoles therapeutic use, Lymphocytes immunology, Male, Mice, Mice, Inbred C57BL, Microsomes metabolism, Rats, Rats, Sprague-Dawley, Receptors, Lysosphingolipid metabolism, Structure-Activity Relationship, Immunologic Factors chemistry, Indoles chemistry, Receptors, Lysosphingolipid agonists
- 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF