Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists.
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
Department of Drug Discovery, Exelixis, 169 Harbor Way, South San Francisco, California 94083, United States.
Mohamed A
MA
Ibrahim
Henry W B
HW
Johnson
Joon Won
JW
Jeong
Gary L
GL
Lewis
Xian
X
Shi
Robin T
RT
Noguchi
Matthew
M
Williams
James W
JW
Leahy
John M
JM
Nuss
John
J
Woolfrey
Monica
M
Banica
Frauke
F
Bentzien
Yu-Chien
YC
Chou
Anna
A
Gibson
Nathan
N
Heald
Peter
P
Lamb
Larry
L
Mattheakis
David
D
Matthews
Aaron
A
Shipway
Xiang
X
Wu
Wentao
W
Zhang
Sihong
S
Zhou
Geetha
G
Shankar
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D000882:Haplorhini; D057166:High-Throughput Screening Assays; D051379:Mice; D009389:Neovascularization, Pathologic; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors*; D012694:Serine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D023041:Xenograft Model Antitumor Assays
D000577:Amides; D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D049349:Receptors, Lysosphingolipid; D012694:Serine; D011392:Proline