Evindar Ghotas, Bernier Sylvie G, Kavarana Malcolm J, Doyle Elisabeth, Lorusso Jeanine, Kelley Michael S, Halley Keith, Hutchings Amy, Wright Albion D, Saha Ashis K, Hannig Gerhard, Morgan Barry A, Westlin William F
Department of Medicinal Chemistry, Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451, USA.
Bioorg Med Chem Lett. 2009 Jan 15;19(2):369-72. doi: 10.1016/j.bmcl.2008.11.072. Epub 2008 Nov 24.
In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.
在强效和选择性鞘氨醇-1-磷酸受体激动剂的设计中，我们能够基于FTY-720的苯酰胺和苯并咪唑类似物鉴定出两个系列的分子。这些支架中的几个设计分子已证明对S1P受体亚型1与亚型3具有选择性，并在小鼠体内具有出色的活性。两个分子PPI-4621（4b）和PPI-4691（10a）口服给药时表现出剂量依赖性淋巴细胞减少。
