Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor

Daniel J Buzard; Thomas O Schrader; Xiuwen Zhu; Juerg Lehmann; Ben Johnson; Michelle Kasem; Sun Hee Kim; Andrew Kawasaki; Luis Lopez; Jeanne Moody; Sangdon Han; Yinghong Gao; Jeff Edwards; Jeremy Barden; Jayant Thatte; Joel Gatlin; Robert M Jones

doi:10.1016/j.bmcl.2014.11.089

Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor

Bioorg Med Chem Lett. 2015 Feb 1;25(3):659-63. doi: 10.1016/j.bmcl.2014.11.089. Epub 2014 Dec 9.

Authors

Daniel J Buzard¹, Thomas O Schrader¹, Xiuwen Zhu¹, Juerg Lehmann¹, Ben Johnson¹, Michelle Kasem¹, Sun Hee Kim¹, Andrew Kawasaki¹, Luis Lopez¹, Jeanne Moody¹, Sangdon Han¹, Yinghong Gao¹, Jeff Edwards¹, Jeremy Barden¹, Jayant Thatte¹, Joel Gatlin¹, Robert M Jones¹

Affiliation

¹ Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.

PMID: 25532755
DOI: 10.1016/j.bmcl.2014.11.089

Abstract

Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.

Keywords: Gilenya®; S1P(1); Sphingosine-1-phosphate.

MeSH terms

Animals
Dogs
Drug Design*
Half-Life
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacokinetics
Mice
Protein Binding
Protein Isoforms / agonists
Protein Isoforms / metabolism
Rats
Rats, Sprague-Dawley
Receptors, Lysosphingolipid / agonists*
Receptors, Lysosphingolipid / metabolism
Structure-Activity Relationship

Substances

Indoles
Protein Isoforms
Receptors, Lysosphingolipid