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.
Subject(s)
Antineoplastic Agents/chemistry , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , 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/metabolism , Sphingosine/analogs & derivatives , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity RelationshipABSTRACT
A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound ( 5) was found during a high-throughput screening campaign. Structure-activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.
