Evaluation of Physicochemical Properties Imparted by Fluorinated Peptidomimetics

氟化肽模拟物赋予的理化性质的评价

• 批准号: 8823966
• 负责人: Ryan A Altman
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823966
• 关键词: Adult; Adverse effects; Affect; Agonist; American; Amides; Analgesics; Anxiety; Biological Assay; Blood - brain barrier anatomy; Chemical Structure; Chemicals; Clinical; Computer Simulation; Constipation; Convulsions; Dependence; Development; Diabetes Mellitus; Drug Kinetics; Employment; Enkephalins; Euphoria; Evaluation; Expenditure; Fluorine; Future; Goals; Gold; Heart Diseases; In Vitro; Institute of Medicine (U.S.); Legal; Libraries; Machine Learning; Malignant Neoplasms; Measures; Medical; Medicine; Mental Depression; Methodology; Modeling; Molecular; Morphine; Neuraxis; Neuropeptides; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Pain; Pain management; Patients; Penetration; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Preparation; Productivity; Property; Quality of life; Research; Sedation procedure; Societies; Techniques; Ventilatory Depression; analog; base; biophysical properties; chronic pain; cost; functional group; improved; in vivo; interest; peptidomimetics; public health relevance; research study; screening; small molecule; social; tool; virtual

 DESCRIPTION (provided by applicant): The ability to control pain remains a major problem in medicine and society. According to the Institute of Medicine, chronic pain affects about 100 million American adults, more people than those affected by diabetes, heart disease, and cancer combined. It has been estimated that the costs associated with pain in the USA exceeds $600 billion dollars per year, mainly due to medical treatment and lost productivity. While these expenditures are significant, the costs in terms of suffering and quality of life cannot be adequately calculated. Opioid analgesics, such as morphine and its analogs, have been the mainstay for treatment of pain for thousands of years, and currently represent the "gold-standard" for pain management. However, clinicians are conservative in prescribing, and patients are conservative in taking, opioids due to valid concerns about adverse effects as well as social and legal issues. As a result, pain is often undertreated, and patients continue to suffer. Endogenous peptides regulate activity within the central nervous system (CNS), and are particularly interesting for the treatment of pain, depression and anxiety. Unfortunately, the clinical usage of peptide-based agents is limited by poor physicochemical (PC) and pharmacokinetic (PK) properties, which restrict penetration into the CNS. Therefore, these peptide-based agents cannot be employed clinically for the treatment of pain. The present proposal aims to develop and employ a new fluorination strategy to rationally improve biophysical properties of peptide-based probes with insufficient drug-like properties, and to allow for these probes to enter the CNS.

 描述（由申请人提供）：控制疼痛的能力仍然是医学和社会的一个主要问题。根据医学研究所的数据，慢性疼痛影响着大约 1 亿美国成年人，比患有糖尿病、心脏病和癌症的人数总和还多。据估计，美国每年与疼痛相关的费用超过 6000 亿美元，主要是由于医疗和生产力损失。虽然这些支出很大，但在痛苦和生活质量方面的成本却无法充分计算。阿片类镇痛药，例如吗啡及其类似物，几千年来一直是治疗疼痛的中流砥柱，目前代表了疼痛管理的“黄金标准”。然而，由于对不良反应以及社会和法律问题的合理担忧，临床医生在处方上持保守态度，而患者在服用阿片类药物时也持保守态度。结果，疼痛往往得不到充分治疗，患者继续遭受痛苦。内源性肽调节中枢神经系统 (CNS) 内的活动，对于治疗疼痛、抑郁和焦虑特别有意义。不幸的是，基于肽的药物的临床使用受到较差的物理化学（PC）和药代动力学（PK）特性的限制，这限制了对中枢神经系统的渗透。因此，这些基于肽的药物不能在临床上用于治疗疼痛。本提案旨在开发和采用一种新的氟化策略，以合理改善类药特性不足的基于肽的探针的生物物理特性，并允许 让这些探针进入中枢神经系统。