Fused tricyclic indoles as S1P₁ agonists with robust efficacy in animal models of autoimmune disease.
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.
Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. dbuzard@arenapharm.com
Daniel J
DJ
Buzard
Sangdon
S
Han
Luis
L
Lopez
Andrew
A
Kawasaki
Jeanne
J
Moody
Lars
L
Thoresen
Brett
B
Ullman
Juerg
J
Lehmann
Imelda
I
Calderon
Xiuwen
X
Zhu
Tawfik
T
Gharbaoui
Dipanjan
D
Sengupta
Ashwin
A
Krishnan
Yinghong
Y
Gao
Jeff
J
Edwards
Jeremy
J
Barden
Michael
M
Morgan
Khawja
K
Usmani
Chuan
C
Chen
Abu
A
Sadeque
Jayant
J
Thatte
Michelle
M
Solomon
Lixia
L
Fu
Kevin
K
Whelan
Ling
L
Liu
Hussien
H
Al-Shamma
Joel
J
Gatlin
Minh
M
Le
Charles
C
Xing
Sheryll
S
Espinola
Robert M
RM
Jones
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007155:Immunologic Factors; D007211:Indoles; D049349:Receptors, Lysosphingolipid