发明名称 |
NOVEL AGENTS TARGETING CYP51 |
摘要 |
The invention provides inhibitors of a sterol C14-demethylase, a new series of 4- aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) developed using structure-based drug design as well as structure -property relationship (SPR) analyses. The screening hit starting point, LP 10 (KD < 42 nM; EC50 of 0.65 μ&Mgr;), has been optimized to give the potential leads that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts. Many of the optimized compounds have improved microsome stability, and most are selective against the T. cruzi CYP51 relative to human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 μ&Mgr;). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of several compounds of the invention with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis. Orally active compounds and their cyclodextrin complexes have been shown to be effective against Chagas-infected mice. |
申请公布号 |
WO2015048306(A1) |
申请公布日期 |
2015.04.02 |
申请号 |
WO2014US57483 |
申请日期 |
2014.09.25 |
申请人 |
THE SCRIPPS RESEARCH INSTITUTE;THE REGENTS OF THE UNIVERSITY OF CALIFORNIA;ROUSH, WILLIAM R.;CHOI, JUN YONG;PODUST, LARISSA |
发明人 |
ROUSH, WILLIAM R.;CHOI, JUN YONG;PODUST, LARISSA |
分类号 |
A61K31/4409 |
主分类号 |
A61K31/4409 |
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