Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.
This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.
Zhong
Min
M
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA. mzhong@presidiopharma.com
Shen
Wang
W
Barr
Kenneth J
KJ
Arbitrario
Jennifer P
JP
Arkin
Michelle R
MR
Bui
Minna
M
Chen
Teresa
T
Cunningham
Brian C
BC
Evanchik
Marc J
MJ
Hanan
Emily J
EJ
Hoch
Ute
U
Huen
Karen
K
Hyde
Jennifer
J
Kumer
Jeffery L
JL
Lac
Teresa
T
Lawrence
Chris E
CE
Martell
Jose R
JR
Oslob
Johan D
JD
Paulvannan
Kumar
K
Prabhu
Saileta
S
Silverman
Jeffrey A
JA
Wright
Jasmin
J
Yu
Chul H
CH
Zhu
Jiang
J
Flanagan
W Mike
WM
D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D016169:Lymphocyte Function-Associated Antigen-1; D044005:Tetrahydroisoquinolines; D018799:Intercellular Adhesion Molecule-1