ADME/FORMULATION Core

摘要 ADMET/配方核心(核心C)提供ADME、配方、药代动力学和毒理学 为项目团队提供信息，以便从筛选活动的整个过程中优化命中和线索 良好实验室规范(GLP)和进入研究新药(IND)状态，以便在人体上进行进一步测试。这 CORE以CAMPP财团中的CALIBR为中心，并将与斯克里普斯内部的调查人员密切合作 和其他在药物发现检测方面具有互补能力的机构提供标准化的 和全面的药物分析服务。药物化学核心谱系中的所有计划 对后期导联优化和临床前候选特征的正式命中评估将具有 在这个核心中进行的ADME/制定/PK工作。CAMPP项目的类药物性质测定 在先导优化和先导阶段，对候选药物的早期优化是必不可少的。这个 ADME/能力包括体外吸收、分布、代谢、消除(ADME)图谱(细胞 通透性、血浆蛋白结合、肝微粒体稳定性、药物-药物相互作用试验和体内 啮齿动物和非啮齿动物的药物动力学，制剂开发，体外安全药理学，和非啮齿动物 普洛斯毒理学。将采用包括心脏毒性和致突变性在内的体外安全性测试。体外ADME 分析是重要的，并将朝着更高的吞吐量分析，以进行体外评估的SAR 目的(Tier 1 ADME)，随后进行更复杂的后期分析，如诱变性分析 包括AMES和微核试验(第2级ADME)。该核心将与核心D彻底集成，以 确定化合物的药物暴露、药代动力学/药效学(PK/PD)关系和 来自Med Chem Core B的化合物的配方评估。最后，这个核心将能够准备 具有提交需要GLP的小分子IND的丰富经验的候选药物IND 通过FDA外部实验室审核和Calibr现场考察对啮齿动物和非啮齿动物进行毒理学研究 工作人员。这个核心使用药物开发分析和药代动力学数据产生的数据将被制作 可供项目团队实时使用，以及有关分析和质谱学方法的原始数据。的确有 &gt；在肖恩博士的指导下，拥有50年的集体药物发现、药理学和毒理学经验 约瑟夫。这包括配备四个三重四极杆质谱仪的设施，用于密集的生物分析 支持多个并行化学项目所需的能力。

SUMMARY The ADMET/Formulation Core (Core C) provides ADME, formulation, pharmacokinetics, and toxicology information to inform project teams for optimizing hits and leads from screening campaigns all the way through good laboratory practice (GLP) and into investigational new drug (IND) status for further testing in humans. This core is centered within Calibr in the CAMPP consortium and will interface closely with investigators within Scripps and other institutions who have complementary capabilities in drug discovery assays to provide standardized and comprehensive drug profiling services. All programs within the medicinal chemistry core spectrum from formal hit assessment to late lead optimization and preclinical candidate characterization will have ADME/Formulation/PK work conducted in this core. Determination of drug-like properties of the CAMPP projects in the lead optimization and hit to lead stages is essential for optimization of early hits to drug candidates. The ADME/Capabilities include in vitro absorption, distribution, metabolism, elimination (ADME) profiling (cell permeability, plasma protein binding, hepatic microsomal stability, drug-drug interaction assay and in vivo pharmacokinetics in rodents and non-rodents, formulation development, in vitro safety pharmacology, and non- GLP toxicology. In vitro safety assays including cardiotoxicity and mutagenicity will be employed. In vitro ADME assays are important and will be geared toward higher throughput assays for in vitro assessment for SAR purposed (Tier 1 ADME) followed by more complex assay for later stage profiling, like mutagenicity assays including Ames and micronucleus testing (Tier 2 ADME). This core will be thoroughly integrated with Core D to determine drug exposure pharmacokinetic/pharmacodynamic (PK/PD) relationship of compounds and formulation assessment of compounds coming from Med Chem Core B. Finally, this core will be able to prepare an IND for a drug candidate given the extensive experience in filing small molecule INDs that require GLP toxicology studies in rodents and non-rodents through external lab auditing by FDA and on-site visits by Calibr staff. The data generated by this core using drug development assays and pharmacokinetic data will be made available to project teams in real-time along with raw data on assays and mass spectroscopy methods. There is >50 years of collective drug discovery pharmacology and toxicology experience under the direction of Dr. Sean Joseph. This includes facilities with four triple quadrupole mass spectrometers for the intensive bioanalysis capabilities needed to support multiple parallel chemistry programs.