Development of small molecule Limk inhibitors for probing ocular diseases

描述（由申请人提供）：Lim激酶（Limk）是丝氨酸/苏氨酸激酶，其通过肌动蛋白结合蛋白、肌动蛋白解聚因子（ADF）和cofilin的磷酸化和失活来调节微管稳定性和肌动蛋白聚合。Limk同种型Limk 1或Limk 2的异常表达涉及与多种疾病相关的许多功能障碍，例如青光眼、眼部炎症、癌症、原发性肺动脉高压、颅内动脉瘤、阿尔茨海默病和威廉姆斯综合征。Lim激酶是Rho激酶（ROCK）的下游效应子。近年来，ROCK抑制剂已被证明可有效降低眼内压（IOP），并且认为ROCK抑制剂的这种作用是通过Limk途径。与具有多个底物的Rho激酶不同，Lim激酶充当信号整合点并将此信息引导至选定的少数底物，这使得Lim激酶成为药物发现的良好靶标，具有少得多的潜在副作用。尽管Limk抑制剂具有吸引人的潜力，但在同行评审的出版物中还没有报道同时显示出良好的效力、高选择性、良好的溶解度和用于眼部和/或其他CNS应用的适当DMPK性质（例如良好的眼部和/或脑部渗透性质）的小分子抑制剂。在本申请中，我们提出开发基于苯并咪唑支架的新型小分子Limk抑制剂。通过在两年内合成和评估总共约100种化合物，我们预计会发现Limk抑制剂，其生物化学IC 50值< 20 nM，基于细胞的IC 50值< 200 nM，具有良好的选择性，优异的溶解性，并具有良好的眼和/或脑渗透性能。这些化合物将作为有用的分子工具，研究Limk的生物学功能，并探测眼部疾病和其他Limk相关的中枢神经系统疾病。)

DESCRIPTION (provided by applicant): Lim kinases (Limk) are serine/threonine kinases which regulate microtubule stability and actin polymerization by phosphorylation and inactivation of actin binding proteins, the actin depolymerizing factor (ADF) and cofilin. The abnormal expression of either Limk isoform, Limk1 or Limk2, is implicated in numerous malfunctions that are related to a variety of diseases, such as glaucoma, ocular inflammation, cancer, primary pulmonary hypertension, intracranial aneurysms, Alzheimer's disease, and Williams syndrome. Lim kinases are downstream effectors of Rho kinases (ROCK). ROCK inhibitors have been demonstrated to be effective in reducing intraocular pressure (IOP) in recent years, and it is believed that this effect of ROCK inhibitors is through the Limk pathway. Unlike Rho kinases which have multiple substrates, Lim kinases serve as points of signal integration and channel this information to a select few substrates, which makes Lim kinases good targets for drug discovery with much less potential side effects. Despite the attractive potential of Limk inhibitors, there have been no small molecule inhibitors reported in peer-reviewed publications which showed simultaneously good potency, high selectivity, good solubility and appropriate DMPK properties for ocular and/or other CNS applications (such as good eye and/or brain penetration properties). In this application, we propose to develop novel small molecule Limk inhibitors based on a benzimidazole scaffold. Through the synthesis and evaluation of approximately 100 compounds total in two years, we anticipate discovering Limk inhibitors with biochemical IC50 values of < 20 nM, cell-based IC50 values of < 200 nM, good selectivity, excellent solubility, and with good eye and/or brain penetration properties. These compounds will serve as useful molecular tools to study the biological functions of Limk, and to probe ocular diseases and other Limk related CNS diseases. )