ADME/FORMULATION Core

ADME/配方核心

• 批准号: 10514321
• 负责人: Sean B. Joseph
• 金额: $ 422.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514321
• 关键词: Agonist; Ames Assay; Animals; Binding Proteins; Biochemical; Biological; Biological Assay; Calcium ion; Canis familiaris; Cardiac; Cardiotoxicity; Cells; Chemistry; Complement; Complex; Computer software; Cytochrome P450; Data; Data Analytics; Databases; Development; Dose; Drug Design; Drug Exposure; Drug Interactions; Drug Kinetics; Drug usage; Ensure; Enzymes; Excretory function; Formulation; Glucuronides; Hepatic; Hepatocyte; Human; In Vitro; Industrialization; Institution; Investigational Drugs; Ion Channel Gating; Laboratories; Laboratory Procedures; Lead; Length; Mass Spectrum Analysis; Measures; Medicine; Metabolism; Methods; Micronucleus Tests; Microsomes; Mus; Nuclear Receptors; Parents; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology and Toxicology; Phase; Plasma Proteins; Property; Protein Isoforms; Rattus; Reporter Genes; Research; Research Personnel; Risk; Rodent; Safety; Secure; Series; Services; Site Visit; Standardization; Testing; Time; Toxic effect; Toxicology; Work; absorption; analog; assay development; base; candidate selection; cloud based; drug candidate; drug discovery; drug metabolism; drug testing; efficacy study; expectation; experience; good laboratory practice; high throughput screening; improved; in vitro Assay; in vivo; inhibitor; lead optimization; mass spectrometer; micronucleus; novel; pandemic preparedness; potassium ion; pre-clinical; preclinical study; programs; receptor; safety study; scale up; screening; small molecule; tool

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.

总结 ADMET/制剂核心（核心C）提供ADME、制剂、药代动力学和毒理学 为项目团队提供信息，以优化筛选活动中的点击率和潜在客户， 药物非临床研究质量管理规范（GLP）和研究性新药（IND）状态，用于进一步的人体试验。这 核心是以CAMPP联盟的Calibr为中心，并将与Scripps内部的研究人员密切联系 以及其他在药物发现检测方面具有互补能力的机构， 和全面的药物分析服务。药物化学核心范围内的所有程序， 从正式的命中评估到后期的电极导线优化和临床前候选物表征， ADME/制剂/PK工作在此核心中进行。CAMPP项目的类药物性质测定 在先导药物优化和先导药物命中阶段中，对于优化候选药物的早期命中至关重要。的 ADME/能力包括体外吸收、分布、代谢、消除（ADME）分析（细胞 渗透性、血浆蛋白结合、肝微粒体稳定性、药物相互作用试验和体内试验 啮齿动物和非啮齿动物中的药代动力学、制剂开发、体外安全药理学和非 GLP毒理学。将采用体外安全性试验，包括心脏毒性和致突变性。体外adme 分析很重要，将面向更高通量的SAR体外评估分析 目的（第1层ADME），然后进行更复杂的试验，用于后期分析，如致突变性试验 包括艾姆斯和微核试验（2级ADME）。该核心将与核心D完全集成， 确定化合物的药物暴露药代动力学/药效学（PK/PD）关系，以及 来自Med Chem Core B的化合物的制剂评估。最后，这个核心将能够准备 考虑到在提交需要GLP的小分子IND方面的丰富经验， 通过FDA的外部实验室审核和Calibr的现场访问，在啮齿动物和非啮齿动物中进行毒理学研究 工作人员该核心使用药物开发试验和药代动力学数据生成的数据将 可供项目团队实时沿着分析和质谱方法的原始数据。有 >在Sean博士的指导下，拥有50年的药物发现药理学和毒理学经验 Joseph.这包括配备四台三重四极杆质谱仪的设施，用于密集的生物分析 支持多个并行化学程序所需的能力。