Non-peptide Mu Opioid Receptor Selective Antagonists

 描述（由申请人提供）：阿片类药物是癌症和非癌症疼痛管理的主要药物。然而，它们的使用通常与多种不良反应有关，如药物依赖、呼吸抑制、头晕、尿潴留和便秘。其中，最常见和持续的可能是阿片类药物诱导的便秘（OIC）。OIC的患病率在所调查的各种人群中非常高。此外，与阿片类药物的其他不良反应不同，对便秘的耐受性发展是最小的，因此问题仍然存在，并随着剂量的增加而增加。外周限制性莫尔拮抗剂可减轻OIC的症状而不损害阿片类药物的镇痛作用。然而，各种不良反应与现有的外周阿片类药物拮抗剂，这阻碍了他们的应用，并证明在这一类别中寻找新的化学实体。我们假设具有外周选择性活性的高选择性莫尔拮抗剂将是进一步开发OIC治疗的合适候选药物。三个综合的具体目标将测试这个中心假设：1）设计和合成新的配体作为高选择性的外周莫尔拮抗剂。2)以渐进的方式使用体外测定法确定作为外周限制性莫尔拮抗剂的新配体的结合亲和力、功效和基本生物制药/代谢性质; 3）检查新先导物的体内功效、功效和PK/PD特征，并与已知药物进行比较，以鉴定用于进一步临床前和临床研究的候选药物用于OIC治疗。

 DESCRIPTION (provided by applicant): Opioids are the mainstay for cancer and non-cancer pain management. However, their use is often associated with multiple adverse effects such as drug dependence, respiratory depression, dizziness, urinary retention, and constipation. Among these, the most common and persistent one is probably opioid-induced constipation (OIC). The prevalence of OIC is very high in various populations investigated. Moreover, unlike other adverse effects of opioids, tolerance development to constipation is minimal, and therefore the problem persists and worsens with dose escalation. Peripherally restricted MOR antagonists may alleviate the symptoms of OIC without compromising the analgesic effects of opioids. However, various adverse effects are associated with existing peripheral opioid antagonists, which hinder their application and justify the search for new chemical entities in this category. We hypothesize that a highly selective MOR antagonist with peripherally selective activity will be a suitable drug candidate for further development as an OIC treatment. Three integrated specific aims will test this central hypothesis: 1) to design and synthesize novel ligands as highl selective peripheral MOR antagonists. 2) to determine binding affinity, efficacy, and basic biopharmaceutical/metabolic properties of the new ligands as peripherally restricted MOR antagonists using in vitro assays in a progressive manner; 3) to examine the in vivo potency, efficacy, and PK/PD profiles of novel leads and compare with known drugs to identify drug candidates for further preclinical and clinical studies for OIC treatment.