Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase

…, L de Garavilla, J Hall, LK Minor, Y Wang…

文献索引：Greco, Michael N.; Hawkins, Michael J.; Powell, Eugene T.; Almond Jr., Harold R.; De Garavilla, Lawrence; Hall, Jeffrey; Minor, Lisa K.; Wang, Yuanping; Corcoran, Thomas W.; Di Cera, Enrico; Cantwell, Angelene M.; Savvides, Savvas N.; Damiano, Bruce P.; Maryanoff, Bruce E. Journal of Medicinal Chemistry, 2007 , vol. 50, # 8 p. 1727 - 1730

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被引用次数: 37

摘要

A series of β-carboxamido-phosphon (in) ic acids (2) was identified as a new structural motif for obtaining potent inhibitors of human mast cell chymase. For example, 1-naphthyl derivative 5f had an IC50 value of 29 nM and (E)-styryl derivative 6g had an IC50 value of 3.5 nM. An X-ray structure for 5f⊙ chymase revealed key interactions within the enzyme active site. Compound 5f was selective for inhibiting chymase versus eight serine ...