A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists.
Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.
Hale
Jeffrey J
JJ
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. jeffrey_hale@merck.com
Lynch
Christopher L
CL
Neway
William
W
Mills
Sander G
SG
Hajdu
Richard
R
Keohane
Carol Ann
CA
Rosenbach
Mark J
MJ
Milligan
James A
JA
Shei
Gan-Ju
GJ
Parent
Stephen A
SA
Chrebet
Gary
G
Bergstrom
James
J
Card
Deborah
D
Ferrer
Marc
M
Hodder
Peter
P
Strulovici
Berta
B
Rosen
Hugh
H
Mandala
Suzanne
S
D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D004285:Dogs; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008253:Macaca mulatta; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013329:Structure-Activity Relationship
D001384:Azetidines; D007166:Immunosuppressive Agents; D049349:Receptors, Lysosphingolipid; D016244:Guanosine 5'-O-(3-Thiotriphosphate)