期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 4, 页码 1126-1143出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm801421q
关键词
-
资金
- NIH [GM41916]
- New Zealand Foundation for Research
- Science Technology
ImmH (1) and DADMe-ImmH (2) are potent inhibitors of human purine nucleoside phoshorylase (PNP), developed by us and currently in clinical trials for the treatment of a variety of T-cell related diseases. Compounds 1 and 2 were used as templates for the design and synthesis of a series of acyclic immucillin analogues (8-38) in order to identify simplified alterriatives to 1 and 2. SerMe-ImmG (8) and DATMe-ImmG (9) displayed the lowest inhibition constants of 2.1 and 3.4 pM, respectively, vs PNP. It was postulated that the flexible natures of 8 and 9 enabled them to adopt conformations resembling those of I and 2 within the active site of PNP and that the positioning of two hydroxyl groups was critical for picomolar activity. SerMe-ImmH (10, K-d = 5.2 pM) was shown to be orally available in mice with a long biological residence time on blood PNP.
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