Pharmacological validation of adenylyl cyclase 1 as a drug target for chronic pain

腺苷酸环化酶 1 作为慢性疼痛药物靶点的药理学验证

基本信息

批准号：
10548818
负责人：
Daniel Patrick Flaherty
金额：
$ 37.59万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548818
关键词：
Acute Adenylate Cyclase Animal Model Behavioral Assay Biological Assay Biological Availability Chemicals Chronic inflammatory pain Collection Communities Cyclic AMP Dependence Development Drug Industry Drug Kinetics Drug Targeting Drug usage Evaluation Exhibits Freund&apos s Adjuvant G-Protein-Coupled Receptors Genetic Genetic study Goals Health Hyperactivity In Vitro Inflammatory Knockout Mice Lead Literature Mediating Molecular Probes Mus Neurobiology Neurologic Neuronal Plasticity Neurons Neuropathy New Agents Opiate Addiction Opioid Pain Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Production Property Protein Isoforms Pyrimidinones Rattus Reporting Research Research Personnel Rewards Risk Series Solubility Specificity Structure-Activity Relationship Testing Therapeutic Time Tissues Toxic effect Validation War Withdrawal addiction adenylyl cyclase 1 analog aqueous chronic pain chronic pain management chronic painful condition clinical development conditioned place preference cost design improved in vitro Model in vivo inflammatory pain inhibitor knockout animal lead optimization mouse model nanomolar new therapeutic target novel opioid withdrawal pain processing painful neuropathy pharmacologic pre-clinical preclinical study prevent response scaffold screening side effect small molecule inhibitor small molecule libraries tool

项目摘要

Chronic pain costs the US more than $635 billion per year, however, patients fail to receive adequate relief from the available drugs and often become drug-dependent. These observations highlight the importance for identifying new agents acting on unique targets to treat chronic pain. Genetic, neurobiological, and preclinical studies have suggested that adenylyl cyclase type 1 (AC1) may provide that new drug target. AC1 knock out mice (AC1-/-) show reduced or absent inflammatory and neuropathic pain when compared to littermate controls. Preclinical studies with a small molecule inhibitor of AC1, NB001 revealed that NB001 reduced chronic pain responses (i.e. inflammatory and neuropathic) in both mice and rats. Similarly, we have recently shown that a novel AC1 inhibitor, ST034307 also reduced inflammatory pain in a mouse model. These studies are consistent with the premise that AC1 is a new target for inhibitors of chronic pain. Unfortunately, both NB001 and ST034307 have significant issues and liabilities preventing further development. To that end, we have recently screened a chemical library collection that allowed us to identify a pyrimidinone scaffold for the development of novel AC1 inhibitors. This scaffold was prioritized for hit-to-lead optimization based on several promising criteria. Preliminary structure-activity relationship (SAR) studies have revealed for the first time compounds with sub-micromolar potency at AC1, as well as selectivity versus the closely-related AC8. Further, initial in vivo studies with a lead compound reveal activity in an animal model of chronic pain. Despite these promising observations, the lead compounds suffer from extremely low aqueous solubility. We propose medicinal chemistry optimization of this scaffold to develop potent and selective inhibitors of AC1 activity as novel probes under the following Specific Aims: Specific aim 1 will use medicinal chemistry optimization of the pyrimidinone scaffold to develop potent drug-like AC1-selective molecular probes. Specific aim 2 will establish the pharmacological specificity of the probe molecules using a set of in vitro model assays and explore the mechanisms for probe activity. Additionally, we will execute in vivo preclinical pharmacokinetic testing with iterative medicinal chemistry and pharmacology. Specific aim 3 will then use the best molecules to explore the in vivo pharmacological activity of the AC1 inhibitors in a mouse model of inflammatory pain, conditioned place preference, and opioid withdrawal. At the end of this study, we shall provide the research community with chemical probes with < 100 nM AC1 potency, > 30-fold selectivity vs other ACs and related CNS targets, and in vivo efficacy. These new probes will provide essential tools to validate AC1 as a new and safe drug target in the treatment of chronic pain.

但是，慢性疼痛每年花费美国超过6350亿美元，但是患者无法获得足够的救济从可用的药物中，经常依赖药物。这些观察强调了识别作用于独特目标以治疗慢性疼痛的新药物。遗传学，神经生物学和临床前研究表明，腺苷酸环化酶1型（AC1）可以提供新的药物靶标。 AC1淘汰与同窝对照相比，小鼠（AC1 - / - ）显示出炎症和神经性疼痛的减少或缺失。 NB001用小分子抑制剂进行临床前研究表明，NB001减少了慢性疼痛小鼠和大鼠的反应（即炎症和神经性）。同样，我们最近表明新型的AC1抑制剂，ST034307还减少了小鼠模型中的炎症性疼痛。这些研究是一致的以这样的前提是AC1是慢性疼痛抑制剂的新靶标。不幸的是，NB001和ST034307都有重大问题和责任，以防止进一步发展。为此，我们最近筛选了化学库集合，使我们能够识别出新型AC1开发的嘧啶酮支架抑制剂。根据几个有前途的标准，将此脚手架优先考虑命中率优化。初步的结构活性关系（SAR）研究首次揭示了与亚微摩尔的化合物 AC1的效力以及选择性与密切相关的AC8。此外，最初的体内研究铅化合物在慢性疼痛的动物模型中揭示了活性。尽管有这些有希望的观察，但领先化合物的水溶性极低。我们建议对此进行药物化学优化脚手架以在以下特异性下发展为AC1活性的有效和选择性抑制剂作为新型探针目的：特定目标1将使用嘧啶酮支架的药物化学优化来发展有效药物样的AC1选择性分子探针。具体目标2将确定该药理特异性探针分子使用一组体外模型测定法，并探索探针活性的机制。此外，我们将使用迭代药物化学和药理学执行体内临床前药代动力学测试。然后，特定的目标3将使用最佳分子探索AC1抑制剂的体内药理活性在炎症性疼痛的小鼠模型中，有条件的位置偏好和阿片类药物戒断。最后研究，我们将为研究界提供<100 nm AC1效力，> 30倍的化学探针选择性与其他ACS和相关的CNS靶标，以及体内功效。这些新探测器将提供必需品验证AC1作为治疗慢性疼痛的新型药物目标的工具。