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.

慢性疼痛每年给美国造成超过 6350 亿美元的损失，但患者却未能得到足够的缓解远离可用药物，并且常常变得药物依赖。这些观察强调了确定作用于独特靶点的新药物来治疗慢性疼痛。遗传学、神经生物学和临床前研究表明1型腺苷酸环化酶（AC1）可能提供这种新的药物靶点。 AC1 敲除与同窝对照小鼠相比，AC1-/- 小鼠的炎症和神经性疼痛减轻或消失。 AC1 小分子抑制剂 NB001 的临床前研究表明，NB001 可减轻慢性疼痛小鼠和大鼠的反应（即炎症和神经病理性）。同样，我们最近证明了新型 AC1 抑制剂 ST034307 还可以减轻小鼠模型中的炎症疼痛。这些研究是一致的前提是 AC1 是慢性疼痛抑制剂的新靶点。不幸的是，NB001和ST034307 存在阻碍进一步发展的重大问题和责任。为此，我们最近筛选了化学库集合使我们能够确定用于开发新型 AC1 的嘧啶酮支架抑制剂。根据几个有希望的标准，该支架被优先用于命中到先导优化。初步的构效关系（SAR）研究首次揭示了亚微摩尔化合物 AC1 的效力，以及与密切相关的 AC8 相比的选择性。此外，初步体内研究化合物揭示了慢性疼痛动物模型的活性。尽管有这些有希望的观察结果，但领先的化合物的水溶性极低。我们建议对此进行药物化学优化支架开发有效的和选择性的 AC1 活性抑制剂作为新探针在以下特定条件下目标：具体目标 1 将利用嘧啶酮支架的药物化学优化来开发有效的类药物 AC1 选择性分子探针。具体目标 2 将确定该药物的药理学特异性使用一组体外模型测定探针分子并探索探针活性的机制。此外，我们将通过迭代药物化学和药理学进行体内临床前药代动力学测试。具体目标3随后将使用最好的分子来探索AC1抑制剂的体内药理活性在炎症性疼痛、条件性位置偏好和阿片类药物戒断的小鼠模型中。在这最后研究，我们将为研究界提供 < 100 nM AC1 效力、 > 30 倍的化学探针与其他 AC 和相关 CNS 靶点相比的选择性，以及体内功效。这些新探针将提供必要的验证 AC1 作为治疗慢性疼痛的新的安全药物靶点的工具。