Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents

详细信息    查看全文

• 作者：Jun Yong Choi ; Claudia M. Calvet ; Shamila S. Gunatilleke ; Claudia Ruiz ; Michael D. Cameron ; James H. McKerrow ; Larissa M. Podust ; William R. Roush
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 10, 2013
• 年：2013
• 卷：56
• 期：19
• 页码：7651-7668
• 全文大小：784K
• 年卷期：v.56,no.19(October 10, 2013)
• ISSN：1520-4804

文摘

A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure鈥損roperty relationship (SPR) analyses. The screening hit starting point, LP10 (K_D 鈮?42 nM; EC₅₀ = 0.65 渭M), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC₅₀ = 14鈥?8 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 渭M). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.