Evaluation of Physicochemical Properties Imparted by Fluorinated Peptidomimetics

 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，比糖尿病，心脏病和癌症的总和还要多。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。虽然这些支出数额巨大，但无法充分计算在痛苦和生活质量方面的代价。阿片类镇痛药，如吗啡及其类似物，几千年来一直是治疗疼痛的主要药物，目前代表了疼痛管理的“金标准”。然而，由于对不良反应以及社会和法律的问题的合理担忧，临床医生在处方方面持保守态度，患者在服用阿片类药物方面持保守态度。因此，疼痛往往得不到充分治疗，患者继续受苦。内源性肽调节中枢神经系统（CNS）内的活性，并且对于疼痛、抑郁和焦虑的治疗特别感兴趣。不幸的是，肽类药物的临床应用受到物理化学（PC）和药代动力学（PK）性质差的限制，这限制了其渗透到CNS中。因此，这些基于肽的药剂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生物物理学策略，以合理地改善具有不足的药物样性质的基于肽的探针的生物物理性质，并允许 让这些探针进入中枢神经系统

 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.