Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.
Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.
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DOI：
10.1021/acs.jmedchem.1c01995
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发表时间：
2022-03-10
影响因子：
7.3
通讯作者：
Sarko, Christopher
中科院分区：
文献类型：
--
作者：
Taft, Benjamin R.;Yokokawa, Fumiaki;Kirrane, Tom;Mata, Anne-Catherine;Huang, Richard;Blaquiere, Nicole;Waldron, Grace;Zou, Bin;Simon, Oliver;Vankadara, Subramanyam;Chan, Wai Ling;Ding, Mei;Sim, Sandra;Straimer, Judith;Guiguemde, Armand;Lakshminarayana, Suresh B.;Jain, Jay Prakash;Bodenreider, Christophe;Thompson, Christopher;Lanshoeft, Christian;Shu, Wei;Fang, Eric;Qumber, Jafri;Chan, Katherine;Pei, Luying;Chen, Yen-Liang;Schulz, Hanna;Lim, Jessie;Abas, Siti Nurdiana;Ang, Xiaoman;Liu, Yugang;Angulo-Barturen, Inigo;Belen Jimenez-Diaz, Maria;Javier Gamo, Francisco;Crespo-Fernandez, Benigno;Rosenthal, Philip J.;Cooper, Roland A.;Tumwebaze, Patrick;Campos Aguiar, Anna Caroline;Campo, Brice;Campbell, Simon;Wagner, Jurgen;Diagana, Thierry T.;Sarko, Christopher
利用血期恶性疟原虫（Pf）生长抑制试验，通过表型高通量筛选，鉴定了一系列5-芳基-2-氨基咪唑噻二唑（ITD）衍生物。一个主要的优化项目专注于提高抗疟原虫效力、对人类激酶的选择性、吸收、分布、代谢、排泄和毒性特性以及扩展的药理学特征，最终确定了INE963(1)。对Pf 3D7 （EC50 = 0.006 μM）具有较强的细胞活性，体外达到“青蒿素样”杀伤动力学，寄生虫清除时间<24 h。单次剂量30 mg/kg对Pf人源化严重联合免疫缺陷小鼠模型完全治愈。INE963(1)在药物选择研究中也表现出高的耐药屏障和跨物种的长半衰期（T1/2）。这些特性表明，INE963(1)具有巨大的潜力，可以用短剂量方案治疗简单的疟疾。因此，INE963(1)通过GLP毒理学研究取得进展，目前正在进行Ph1临床试验。
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) 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 INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 μM) and achieves “artemisinin-like” kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.
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DOI：
10.1016/s1473-3099(21)00252-8
发表时间：
2021-12
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
McCarthy JS;Yalkinoglu Ö;Odedra A;Webster R;Oeuvray C;Tappert A;Bezuidenhout D;Giddins MJ;Dhingra SK;Fidock DA;Marquart L;Webb L;Yin X;Khandelwal A;Bagchus WM
通讯作者：
Bagchus WM
影响因子：
3
作者：
Linares, Maria;Viera, Sara;Gamo, Francisco-Javier
通讯作者：
Gamo, Francisco-Javier
影响因子：
158.5
作者：
White, Nicholas J.;Pukrittayakamee, Sasithon;Leong, F. Joel
通讯作者：
Leong, F. Joel
影响因子：
4.9
作者：
Belen Jimenez-Diaz, Maria;Mulet, Teresa;Angulo-Barturen, Inigo
通讯作者：
Angulo-Barturen, Inigo
影响因子：
3
作者：
Avery VM;Bashyam S;Burrows JN;Duffy S;Papadatos G;Puthukkuti S;Sambandan Y;Singh S;Spangenberg T;Waterson D;Willis P
通讯作者：
Willis P