Discovery of an Orexin-1 receptor antagonist for treatment of cocaine addiction and dependence

 描述(申请人提供)：该计划的目标是确定一种人的食欲素-1受体拮抗剂，适合开发用于治疗可卡因成瘾。此前，下丘脑食欲素系统在物质寻求和渴求中的作用已经被免疫组织化学证明，当条件动物接受可卡因、吗啡或食物的暗示时，下丘脑外侧的食欲素生成神经元被激活；此外，当寻求奖赏行为消失时，可以通过注射食欲素激动剂来恢复，并可以被选择性食欲素-1受体拮抗剂SB-334867阻断。到目前为止，由于药物性质较差，还没有选择性的OX1R拮抗剂进入临床研究。我们已经确定了OX1R的有效拮抗剂，其选择性高达OX2R的40倍。这些都是用基于结构的药物发现方法进行优化的有希望的起点，以实验确定的配体-受体复合体的结构为指导。本项目的主要目标是选择一种高选择性的增食欲素-1受体拮抗剂作为临床治疗可卡因成瘾的候选药物。这一目标将通过优化Heptares已经确定的选择性OX1R拮抗剂、改进它们的效力、选择性和ADMET特性、在成瘾动物模型中证明它们的有效性以及通过临床前开发开发最有前途的分子来实现。如果主要目标无法实现，一个辅助目标是选择一种高度选择性的食欲素-1受体拮抗剂作为治疗尼古丁成瘾的临床开发的候选药物。目的1-优化目前OX1R选择性拮抗剂的先导系列，以进行疗效测试。这将包括迭代 铅分子的优化，配体-受体复合体的结晶，结合和功能抑制的亲和力和动力学的测量，体外DMPK和体内DMPK的表征。目的2-评价化合物在成瘾动物模型中的体内疗效。合适的模型已经被开发出来，并被证明对食欲素-1拮抗剂的给药敏感。这一目的将验证优化的食欲素-1拮抗剂(S)在大鼠大脑中显示靶向参与，以及在可卡因(和尼古丁)成瘾大鼠模型中的有效性。目标3-通过临床前开发使候选药物进展到可以进行临床研究的程度。候选药物的合成将扩大规模，并将接受详细的配方、DMPK和毒理学研究，从而能够提交IND申请。

 DESCRIPTION (provided by applicant): The objective of this program is to identify a human Orexin-1 receptor antagonist which is suitable for development as a treatment for cocaine addiction. The role of the hypothalamic Orexin system in substance seeking and craving has been previously shown using immunohistochemistry to demonstrate activation of orexigenic neurons in the lateral hypothalamus when conditioned animals received cues for cocaine, morphine or food; in addition, when the reward seeking behavior was extinguished, it could be reinstated by administration of an Orexin agonist, and could be blocked by the selective Orexin-1 receptor (OX1R) antagonist SB-334867. To date there have been no selective OX1R antagonists taken forward into clinical studies due to poor pharmaceutical properties. We have identified potent antagonists of OX1R with up to 40- fold selectivity over OX2R. These are promising starting points for optimization with a structure-based drug discovery approach, guided by experimentally determined structures of ligand-receptor complexes. The primary goal of this project is to select a highly selective Orexin-1 receptor antagonist as a candidate drug fo clinical development to treat cocaine addiction. This goal will be achieved through optimization of selective OX1R antagonists already identified by Heptares, refining their potency, selectivity, and ADMET properties, demonstrating their efficacy in animal models of addiction, and progressing the most promising molecule through pre-clinical development. A subsidiary goal, should the primary be unattainable, is to select a highly selective Orexin-1 receptor antagonist as a candidate drug for clinical development to treat nicotine addiction. Aim 1 - To optimize the current lead series of OX1R selective antagonists for efficacy testing. This will include iterative optimization of lead molecules, crystallization of ligand-receptor complexes, measuring the affinity and kinetics of binding and functional inhibition, in vitro DMPK and in vivo DMPK characterization. Aim 2 - To evaluate the in vivo efficacy of compounds in animal models of addiction. Suitable models have been developed and demonstrated to be sensitive to the administration of Orexin-1 antagonists. This aim will validate that the optimized Orexin-1 antagonist(s), show target engagement in rat brain, and efficacy in rat models of cocaine (and nicotine) addiction. Aim 3 - To progress the drug candidate through pre-clinical development to a point where it is ready for clinical studies. Synthesis of the drug candidate will be scaled up, and it will be subjected to detailed formulation, DMPK and toxicology studies, enabling submission of an IND application.