Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists

Ghotas Evindar; Sylvie G Bernier; Elisabeth Doyle; Malcolm J Kavarana; Alexander L Satz; Jeanine Lorusso; Heather S Blanchette; Ashis K Saha; Gerhard Hannig; Barry A Morgan; William F Westlin

doi:10.1016/j.bmcl.2010.02.098

Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists

Bioorg Med Chem Lett. 2010 Apr 15;20(8):2520-4. doi: 10.1016/j.bmcl.2010.02.098. Epub 2010 Mar 3.

Authors

Ghotas Evindar¹, Sylvie G Bernier, Elisabeth Doyle, Malcolm J Kavarana, Alexander L Satz, Jeanine Lorusso, Heather S Blanchette, Ashis K Saha, Gerhard Hannig, Barry A Morgan, William F Westlin

Affiliation

¹ Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, Waltham, MA 02451, USA. ghotas.x.evindar@gsk.com

PMID: 20304639
DOI: 10.1016/j.bmcl.2010.02.098

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.

MeSH terms

Administration, Oral
Amino Alcohols / administration & dosage
Amino Alcohols / pharmacology*
Animals
Mice
Receptors, Lysosphingolipid / agonists*
Structure-Activity Relationship

Substances

Amino Alcohols
Receptors, Lysosphingolipid