Discovery of Small Molecules as Antimalarial Agents

作为抗疟剂的小分子的发现

基本信息

批准号：
10312722
负责人：
Shuren Zhu
金额：
$ 25.65万
依托单位：
CASCADE THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312722
关键词：
Acute Animal Model Animals Antimalarials Area Artemisinins Biological Availability Budgets Chemistry Chloroquine Communicable Diseases Data Development Disease Dose Drug Kinetics Evaluation Exhibits Falciparum Malaria Formulation Generations Growth In Vitro Intravenous Investigational New Drug Application Malaria Maximum Tolerated Dose Mefloquine Modeling Molecular Multi-Drug Resistance Natural Products No-Observed-Adverse-Effect Level Oral Parasite resistance Parasites Pharmaceutical Preparations Phase Plasmodium falciparum Prevalence Primates Prophylactic treatment Rattus Research Resistance Rodent Model Route SCID Mice Small Business Innovation Research Grant Standard Model Testing Therapeutic Therapeutic Agents Therapeutic Index Time Toxic effect Toxicity Tests Work acute toxicity developmental toxicity drug candidate drug development drug discovery drug synthesis efficacy evaluation efficacy study experimental study improved in vitro activity in vivo in vivo evaluation intraperitoneal multidisciplinary neurotoxicity novel novel therapeutics pharmacokinetics and pharmacodynamics phase 1 study phase 2 study pre-clinical preclinical study prevent resistant strain scale up small molecule

Acute Animal Model Animals Antimalarials Area Artemisinins Biological Availability Budgets Chemistry Chloroquine Communicable Diseases Data Development Disease Dose Drug Kinetics Evaluation Exhibits Falciparum Malaria Formulation Generations Growth In Vitro Intravenous Investigational New Drug Application Malaria Maximum Tolerated Dose Mefloquine Modeling Molecular Multi-Drug Resistance Natural Products No-Observed-Adverse-Effect Level Oral Parasite resistance Parasites Pharmaceutical Preparations Phase Plasmodium falciparum Prevalence Primates Prophylactic treatment Rattus Research Resistance Rodent Model Route SCID Mice Small Business Innovation Research Grant Standard Model Testing Therapeutic Therapeutic Agents Therapeutic Index Time Toxic effect Toxicity Tests Work acute toxicity developmental toxicity drug candidate drug development drug discovery drug synthesis efficacy evaluation efficacy study experimental study improved in vitro activity in vivo in vivo evaluation intraperitoneal multidisciplinary neurotoxicity novel novel therapeutics pharmacokinetics and pharmacodynamics phase 1 study phase 2 study pre-clinical preclinical study prevent resistant strain scale up small molecule

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项目摘要

PROJECT SUMMARY The proposed research focuses on the development of novel therapeutic agents for the treatment of malaria caused by P. falciparum. Preliminary studies have discovered novel natural product and derivative molecules with potent in vitro activity against both sensitive and multidrug resistant malaria strains including a newly emerging artemisinin resistant parasite line. New compounds are low in toxicity and possess good therapeutic indice. This SBIR Phase I project aims to obtain proof of concept in vivo PK, efficacy, and toxicity data. Studies include: (I) Scale up isolation and purification of natural product and synthesis of derivative compounds; (II) Pharmacokinetic (PK) studies; (III) In vivo efficacy studies in SCID mouse P. falciparum model; (IV) In vivo evaluation for acute and sub-acute toxicity, developmental toxicity, and neurotoxicity. The novelty of the project is the discovery of new molecular entities. The project involves standard approaches to drug development, but the multidisciplinary team that has been assembled will accelerate the generation of preclinical candidates.

项目摘要拟议的研究重点是开发新型治疗剂，以治疗恶性疟原虫引起的疟疾。初步研究发现了新型的天然产物和衍生产品具有有效体外活性的分子对敏感和多药抗性疟疾菌株，包括新兴新兴的青蒿素抗性寄生虫线。新化合物的毒性低，拥有良好治疗性印度。这个SBIR I期项目旨在获得体内PK，功效和毒性数据。研究包括：（i）扩展天然产物的隔离和纯化以及合成衍生化合物；（ii）药代动力学（PK）研究；（iii）SCID小鼠的体内功效研究。恶意型模型；（iv）体内评估急性和亚急性毒性，发育毒性以及神经毒性。该项目的新颖性是发现了新分子实体。该项目涉及制定药物开发的标准方法，但是组装的多学科团队将加速临床前候选人的产生。