Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists.
Basic Information
ID: ALA1156167
Journal: Bioorg Med Chem Lett
Title: Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists.
Authors: Evindar G, Bernier SG, Doyle E, Kavarana MJ, Satz AL, Lorusso J, Blanchette HS, Saha AK, Hannig G, Morgan BA, Westlin WF.
Abstract: In pursuit of a potent and highly selective sphingosine-1-phosphate receptor agonists with an improved in vivo conversion of the precursor to the active phospho-drug, we have utilized previously reported phenylamide and phenylimidazole scaffolds to identify a selectivity enhancing moiety (SEM) and selectivity enhancing orientation (SEO) within both pharmacophores. SEM and SEO have allowed for over 100 to 500-fold improvement in selectivity for S1P receptor subtype 1 over subtype 3. Utility of SEM and SEO and further SAR study allowed for discovery of a potent and selective preclinical candidate PPI-4955 (21b) with an excellent in vivo potency and dose responsiveness and markedly improved overall in vivo pharmacodynamic properties upon oral administration.
CiteXplore: 20304639
DOI: 10.1016/j.bmcl.2010.02.098
Patent ID: ┄