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
Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel syndrome). The screening of a compound collection led to the identification of a 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, compound I) as a potent and selective JNK inhibitor. Chemistry and structure--activity relationship (SAR) studies performed around this novel kinase-inhibiting motif indicated that the left and central parts of the molecule were instrumental to maintaining potency at the enzyme. Accordingly, we investigated the JNK-inhibiting properties of a number of variants of the right-hand moiety of the molecule, which led to the identification of 2-(benzoylaminomethyl)thiophene sulfonamide benzotriazole (AS600292, compound 50a), the first potent and selective JNK inhibitor of this class which demonstrates a protective action against neuronal cell death induced by growth factor and serum deprivation.
