Abstract
The discovery of a novel series of S1P1 agonists is described. Starting from a micromolar HTS positive, iterative optimization gave rise to several single-digit nanomolar S1P1 agonists. The compounds were able to induce internalization of the S1P1 receptor, and a selected compound was shown to be able to induce lymphopenia in mice after oral dosing.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
-
Administration, Oral
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacokinetics
-
Cell Line, Tumor
-
Drug Discovery
-
Fingolimod Hydrochloride
-
High-Throughput Screening Assays
-
Humans
-
Mice
-
Microsomes, Liver / metabolism
-
Propylene Glycols / chemistry
-
Propylene Glycols / pharmacology
-
Rats
-
Receptors, Lysosphingolipid / agonists*
-
Receptors, Lysosphingolipid / metabolism
-
Sphingosine / analogs & derivatives
-
Sphingosine / chemistry
-
Sphingosine / pharmacology
-
Structure-Activity Relationship
Substances
-
Antineoplastic Agents
-
Propylene Glycols
-
Receptors, Lysosphingolipid
-
Fingolimod Hydrochloride
-
Sphingosine