Medicinal Chemistry Optimization of Anti-Alphaviral Leads and Elucidation of Target and Off Target Engagement

委内瑞拉(VEEV)、西部(Weev)和东部马脑炎病毒(Weev)是 导致人类脑炎的新病原体，但还没有批准的人类疫苗 或用于治疗或预防甲型病毒感染的抗病毒药物。我们的研究目标 包括开发针对这些疾病广谱抗病毒临床候选药物 人类脑炎甲型病毒感染。U19中研究项目1的目标 脑炎甲型病毒治疗卓越中心(CEEAT)计划重点关注 两种不同的小分子支架的先导优化活性 体内治疗效果。具体地说，该项目将通过迭代来改进主要原型 以ADME/PK评估为指导的多参数药物化学优化，细胞培养 和机制研究(研究项目3)和活体评估(研究项目2) 在较高级物种(即大鼠和非人灵长类)中暴露、最佳剂量和安全性。 该项目将管理所有合成化学需求，包括药物化学、非GMP 类似物的比例和验证，化合物在CEEAT实验室的分发点，以及 在实施原料药CRO项目之前实施流程制造改进 合成到高级GLP毒理学研究。此外，公式和稳定性分析 将与UW-Madison Zeeh配方站合作进行。几个 将伴随与原料药以及配方生成和表征有关的活动 通过与Pre-IND要求一致的适当认证和分析，协调和 由CEEAT结构内的产品开发和监管顾问监督。

Venezuelan (VEEV), Western (WEEV), and Eastern Equine Encephalitis viruses (WEEV), are emerging pathogens that cause human encephalitis, yet there are no approved human vaccines or antiviral agents for treating or preventing any alphaviruses infection. Our research objectives include the development of a broad spectrum antiviral clinical candidate against these encephalitic alphavirus infections in humans. The aims of Research Project 1 within the U19 Center of Excellence for Encephalitic Alphavirus Therapeutics (CEEAT) program focus on the lead optimization activities of two distinct small molecule scaffolds with prophylactic and therapeutic in vivo efficacy. Specifically, the project will improve lead prototypes through iterative multi-parameter medicinal chemistry optimization, guided by ADME/PK assessment, cell culture and mechanistic studies (Research Project 3) and in vivo assessments (Research Project 2) for exposure, optimum dosing and safety in higher order species (i.e., rats and non-human primates). The project will manage all synthetic chemistry needs including medicinal chemistry, non-GMP scaling and validation of analogs, point of compound distribution to CEEAT labs, and implementation of process manufacturing improvements prior to CRO engagement for API synthesis to advanced GLP toxicological studies. Additionally, formulation and stability analyses will be conducted, in collaboration with the UW-Madison Zeeh Formulation Station. Several activities pertaining to API and formulation generation and characterization will be accompanied by appropriate certification and analyses in accord with pre-IND requirements, coordinated and overseen by product development and regulatory consultants within the CEEAT structure.