25195-41-9Relevant academic research and scientific papers
Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype-Distinct Screening Hits
Schnute, Mark E.,McReynolds, Matthew D.,Carroll, Jeffrey,Chrencik, Jill,Highkin, Maureen K.,Iyanar, Kaliapan,Jerome, Gina,Rains, John W.,Saabye, Matthew,Scholten, Jeffrey A.,Yates, Matthew,Nagiec, Marek M.
, p. 2562 - 2572 (2017/04/03)
Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with 2 orders of magnitude improved potency. Compound 22a inhibited SphK1 with an IC50 of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail-region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated, yielding SphK1-selective, potent SphK1/2 dual, or SphK2-preferential inhibitors.
Azetidine derivatives, their preparation and medicaments containing them
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, (2008/06/13)
The invention concerns compounds of formula (1) wherein: R represents a chain (A) or (B); R1 is methyl or ethyl; R2 is either an optionally substituted aromatic or an optionally substituted heteroaromatic ring; R3 and R4, identical or different, are either an optionally substituted aromatic or an optionally substituted heteroaromatic ring; R′ represents a hydrogen atom or a —CO—alk radical, their optical isomers, their salts, their preparation and medicines containing them.
