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Synthesis and evaluation of arylalkoxy- and biarylalkoxy-phenylamide and phenylimidazoles as potent and selective sphingosine-1-phosphate receptor subtype-1 agonists |
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| Authors: | Ghotas Evindar Alexander L. Satz Sylvie G. Bernier Malcolm J. Kavarana Elisabeth Doyle Jeanine Lorusso Nazbeh Taghizadeh Keith Halley Amy Hutchings Michael S. Kelley Albion D. Wright Ashis K. Saha Gerhard Hannig Barry A. Morgan William F. Westlin |
| Affiliation: | 1. Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451, United States;2. Department of Preclinical Research, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451, United States |
| Abstract: | In pursuit of potent and selective sphingosine-1-phosphate receptor agonists, we have utilized previously reported phenylamide and phenylimidazole scaffolds to explore extensive side-chain modifications to generate new molecular entities. A number of designed molecules demonstrate good selectivity and excellent in vitro and in vivo potency in both mouse and rat models. Oral administration of the lead molecule 11c (PPI-4667) demonstrated potent and dose-responsive lymphopenia. |
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