2. Academic Validation
  3. Exploration of amino alcohol derivatives as novel, potent, and highly selective sphingosine-1-phosphate receptor subtype-1 agonists

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.
Ghotas Evindar 1,  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
Affiliations

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.

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