Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 5959 Horton Street, Emeryville, California 94608, United States.
Novartis Institute for Tropical Diseases, 10 Biopolis Road, no. 05-01, Chromos, Singapore 138670, Singapore.
J Med Chem. 2022 Mar 10;65(5):3798-3813. doi: 10.1021/acs.jmedchem.1c01995. Epub 2022 Mar 1.
A series of 5-aryl-2-amino-midazohiaiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage () growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of (), which demonstrates potent cellular activity against 3D7 (EC = 0.006 μM) and achieves "artemisinin-like" kill kinetics with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the -humanized severe combined immunodeficient mouse model. () also exhibits a high barrier to resistance in drug selection studies and a long half-life () across species. These properties suggest the significant potential for () to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, () was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.
通过基于表型的高通量筛选，利用红内期生长抑制试验，鉴定出一系列 5-芳基-2-氨基-咪唑并[1,2-a]嘧啶（ITD）衍生物。一个以提高抗疟原虫效力、对人源激酶的选择性、吸收、分布、代谢、排泄和毒性特性以及扩展药理学特性为重点的优化项目，最终确定了 （），它对 3D7 具有很强的细胞活性（EC=0.006 μM），并具有“青蒿素样”的杀伤动力学，寄生虫清除时间<24 小时。在人源化严重联合免疫缺陷小鼠模型中，单次给予 30mg/kg 即可完全治愈。（）在药物选择研究中也表现出对耐药性的高屏障，并且在不同物种中的半衰期（）较长。这些特性表明，（）很有潜力为无并发症疟疾提供一种具有短期给药方案的治愈疗法。基于这些原因，（）通过了 GLP 毒理学研究，并正在进行 Ph1 临床试验。
