Evaluation of Physicochemical Properties Imparted by Fluorinated Peptidomimetics

 描述(申请人提供)：控制疼痛的能力仍然是医学和社会中的一个主要问题。根据医学研究所的数据，慢性疼痛影响了大约1亿美国成年人，比糖尿病、心脏病和癌症患者的总和还要多。据估计，在美国，每年与疼痛相关的成本超过6000亿美元，主要是由于医疗和生产力损失。虽然这些支出数额很大，但无法充分计算痛苦和生活质量方面的成本。阿片类镇痛剂，如吗啡及其类似物，几千年来一直是治疗疼痛的中流砥柱，目前代表着疼痛治疗的“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，临床医生在开处方时是保守的，患者在服用阿片类药物时也是保守的。因此，疼痛往往得不到充分治疗，患者继续遭受痛苦。内源性多肽调节中枢神经系统(CNS)的活动，在治疗疼痛、抑郁和焦虑方面特别有趣。不幸的是，基于多肽的药物的临床应用受到较差的物理化学(PC)和药代动力学(PK)性质的限制，这限制了其对中枢神经系统的渗透。因此，这些基于多肽的药物不能用于临床治疗疼痛。本建议旨在开发和使用一种新的氟化策略，以合理地改善类药物性质不足的多肽探针的生物物理性质，并允许 让这些探测器进入中枢神经系统。

 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.