O'Neill Paul M, Shone Alison E, Stanford Deborah, Nixon Gemma, Asadollahy Eghbaleh, Park B Kevin, Maggs James L, Roberts Phil, Stocks Paul A, Biagini Giancarlo, Bray Patrick G, Davies Jill, Berry Neil, Hall Charlotte, Rimmer Karen, Winstanley Peter A, Hindley Stephen, Bambal Ramesh B, Davis Charles B, Bates Martin, Gresham Stephanie L, Brigandi Richard A, Gomez-de-Las-Heras Federico M, Gargallo Domingo V, Parapini Silvia, Vivas Livia, Lander Hollie, Taramelli Donatella, Ward Stephen A
Department of Chemistry, University of Liverpool, Liverpool, UK.
J Med Chem. 2009 Apr 9;52(7):1828-44. doi: 10.1021/jm8012757.
On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.
基于对4-氨基喹啉阿莫地喹（1b）毒性的机理理解，制备了三个系列的阿莫地喹类似物，其中4-氨基酚“代谢警报”通过用氢、氟或氯原子取代4'-羟基进行了修饰。经过抗疟评估和作用机制研究，选择了两个候选物进行详细的ADME研究以及体外和体内毒理学评估。4'-氟-N-叔丁基阿莫地喹（2k）随后被确定为进一步开发研究的候选物，这是基于其对氯喹敏感和耐药寄生虫具有强效活性、口服生物利用度中等至优异、体外研究毒性低以及安全概况可接受。
