Glenn Matthew P, Chang Sung-Youn, Hornéy Carrie, Rivas Kasey, Yokoyama Kohei, Pusateri Erin E, Fletcher Steven, Cummings Christopher G, Buckner Frederick S, Pendyala Prakash R, Chakrabarti Debopam, Sebti Saïd M, Gelb Michael, Van Voorhis Wesley C, Hamilton Andrew D
Department of Chemistry, Yale University, New Haven, Connecticut 06511, USA.
J Med Chem. 2006 Sep 21;49(19):5710-27. doi: 10.1021/jm060081v.
Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC(50) < 1 nM) and toxicity to cultured parasites at low concentrations (ED(50) < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.
第三世界国家急需获得廉价的治疗方法来应对疟疾造成的高死亡率。在此，我们报告了一类新型的抗疟蛋白法尼基转移酶（PFT）抑制剂，其设计特别注重简单的分子结构，以便基于这个最近得到验证的抗疟靶点轻松获得治疗方法。这一系列新型化合物是首次报道的对恶性疟原虫具有选择性的PFT抑制剂（选择性高达145倍），先导抑制剂在体外显示出优异的活性（IC(50) < 1 nM），并且在低浓度下对培养的寄生虫具有毒性（ED(50) < 100 nM）。本文还报道了吸收、代谢和口服生物利用度的初步研究。
