Development of Novel Therapeutics for Leishmaniasis

利什曼病新疗法的开发

• 批准号: 10059160
• 负责人: Rodney Kiplin Guy
• 金额: $ 44.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-14 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059160
• 关键词: Amphotericin; Animal Model; Bioavailable; Biological Availability; Characteristics; Chemicals; Collection; Communicable Diseases; Cutaneous; Development; Disease; Drug Kinetics; Drug resistance; Ensure; Excretory function; Exhibits; Funding Opportunities; Future; Hamsters; Health; In Vitro; Individual; Infection; Laboratories; Lead; Leishmania; Leishmania donovani; Leishmaniasis; Libraries; Maximum Tolerated Dose; Measures; Metabolism; Methods; Miltefosine; Modeling; Modification; Molecular Target; Monitor; Mus; Oral; Parasite resistance; Parasites; Parasitic Diseases; Paromomycin; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Predisposition; Property; Resistance; Resistance development; Resources; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Tropical Disease; Visceral; Visceral Leishmaniasis; absorption; acute toxicity; analog; chemical property; cost; drug development; drug discovery; efficacy testing; high throughput screening; improved; in vivo; macrophage; mouse model; nanomolar; novel; novel therapeutics; parenteral administration; pathogen; physical property; programs; response; scaffold; success; teratogenesis; tissue culture

PROJECT SUMMARY Relevance. Leishmania parasites infect an estimated 12 million individuals, and no satisfactory treatments are yet available. This proposal will advance 3 scaffolds that have emerged from a phenotypic screen for development of leads towards novel effective orally-bioavailable drugs against leishmaniasis. Summary. A previous phenotypic screen against the disease-causing intracellular amastigote stage of Leishmania parasites has identified 3 chemical scaffolds with potent efficacy against amastigotes. Each hit compound exhibits nanomolar efficacy against amastigotes growing in tissue culture macrophages and has physical and chemical properties suggesting promise for development of a novel orally bioavailable drug. Analogs of each scaffold will be prepared and tested for efficacy against amastigotes in vitro, optimal absorption/distribution/metabolism/excretion/toxicity (ADMET) profiles, acceptable in vivo pharmacokinetics (PK), and efficacy in controlling disease in a murine model of visceral leishmaniasis. Following establishment of initial structure-activity relationships, an extensive medicinal chemistry program will be undertaken to develop analogs with the best overall properties for orally bioavailable drugs and to improve upon any potential deficits that emerge in the original hits. The efficacy of each scaffold against multiple species of Leishmania and against drug resistant field isolates will be tested at an early stage to ascertain the potential of each scaffold for applicability against a broad range of parasites causing distinct types of leishmaniasis and with or without pre-established resistance to other currently employed, albeit non-optimal, antileishmanial drugs. The rate of development of resistance will be monitored to ensure that leads that are pursued will be reasonably stable against emergence of resistance during use in the field. In association with an extensive medicinal chemistry program, in vivo pharmacokinetics and acute toxicity studies and ability to control visceral infections in mice and hamsters will be determined to arrive at the top synthetic leads originating from the original 3 hits. The overall objective is to develop several leads with highly promising characteristics for ultimate development of desperately needed novel and effective drugs against this widespread and poorly controlled parasitic disease.

项目概要 关联。估计有 1200 万人感染利什曼原虫，但目前尚无令人满意的治疗方法 尚未可用。该提案将推进从表型筛选中出现的 3 个支架 开发针对利什曼病的新型有效口服生物药物。概括。一个 之前针对利什曼原虫致病细胞内无鞭毛体阶段进行的表型筛选 已鉴定出 3 种对无鞭毛体具有有效功效的化学支架。每个热门化合物都展示了 对组织培养巨噬细胞中生长的无鞭毛体具有纳摩尔功效，并且具有物理和化学作用 这些特性预示着开发新型口服生物可利用药物的前景。每个支架的类似物将 准备并测试体外对抗无鞭毛体的功效，最佳 吸收/分布/代谢/排泄/毒性 (ADMET) 特征，可接受的体内药代动力学 （PK），以及在内脏利什曼病小鼠模型中控制疾病的功效。成立后 初步的结构-活性关系，将进行广泛的药物化学计划 开发具有最佳整体特性的口服生物可利用药物的类似物，并改进任何潜力 原始热门作品中出现的缺陷。每个支架对多种利什曼原虫的功效 并将在早期阶段针对耐药野外分离株进行测试，以确定每种药物的潜力 适用于对抗多种引起不同类型利什曼病的寄生虫的支架，并且具有或 对目前使用的其他抗利什曼药物（尽管不是最佳的）没有预先确定的耐药性。这 将监测耐药性的发展速度，以确保所追寻的线索将得到合理的处理。 在田间使用过程中稳定，不会出现耐药性。与广泛的药用相关 化学课程、体内药代动力学和急性毒性研究以及控制内脏感染的能力 在小鼠和仓鼠中，将确定来自最初 3 个命中的顶级合成线索。 总体目标是开发几个具有高度前景特征的先导化合物以实现最终开发 迫切需要针对这种广泛且控制不良的寄生虫的新型有效药物 疾病。

项目成果

Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.

• DOI: 10.1371/journal.pntd.0006157
• 发表时间: 2017-12-01
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Ortiz, Diana;Guiguemde, W Armand;Landfear, Scott M
• 通讯作者: Landfear, Scott M

Optimization of Orally Bioavailable Antileishmanial 2,4,5-Trisubstituted Benzamides.

口服生物可利用的抗利什曼尼尔 2,4,5-三取代苯甲酰胺的优化。

• DOI: 10.1021/acs.jmedchem.3c00056
• 发表时间: 2023
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Kim,HoShin;Ortiz,Diana;Kadayat,TaraMan;Fargo,CorinneM;Hammill,JaredT;Chen,Yizhe;Rice,AmyL;Begley,KristinL;Shoeran,Gaurav;Pistel,William;Yates,PhillipA;Sanchez,MarcoA;Landfear,ScottM;Guy,RKiplin
• 通讯作者: Guy,RKiplin

Amino-Substituted 3-Aryl- and 3-Heteroarylquinolines as Potential Antileishmanial Agents.

• DOI: 10.1021/acs.jmedchem.1c00813
• 发表时间: 2021-08-26
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Hammill JT;Sviripa VM;Kril LM;Ortiz D;Fargo CM;Kim HS;Chen Y;Rector J;Rice AL;Domagalska MA;Begley KL;Liu C;Rangnekar VM;Dujardin JC;Watt DS;Landfear SM;Guy RK
• 通讯作者: Guy RK