Department of Chemistry, University of Washington, Seattle, Washington 98195-7185, USA.
J Med Chem. 2010 May 27;53(10):3887-98. doi: 10.1021/jm9013136.
We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.
我们之前报道过，癌症药物临床候选物替匹法尼通过抑制羊毛甾醇 14α-脱甲基酶来阻断麦角甾醇生物合成，从而杀死恰加斯病的病原体克氏锥虫。替匹法尼是人类蛋白法尼基转移酶的抑制剂。我们合成了不再与蛋白法尼基转移酶结合的替匹法尼类似物，并显示出更强的杀伤寄生虫的能力。这是通过在结构指导的方式下改变替匹法尼喹啉环 4 位上的苯基上的取代基，并将氨基用 OMe 取代来实现的。发现了几种能够以亚纳摩尔浓度杀死克氏锥虫且不抑制蛋白法尼基转移酶的化合物。与其他羊毛甾醇 14α-脱甲基酶抑制剂相比，这些化合物显示出仅对人细胞色素 P450（3A4）的抑制作用适度，具有优势。由于替匹法尼具有较高的口服生物利用度和可接受的药代动力学特性，因此新发现的替匹法尼类似物是开发治疗恰加斯病药物的理想先导化合物。
