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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 |
| Institution: | 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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