University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study (UGCCAS), Panjab University, Chandigarh 160014, India.
Curr Med Chem. 2020;27(14):2222-2256. doi: 10.2174/0929867325666181031102829.
Glaucoma is a progressive optic neuropathy causing visual impairment and Retinal Ganglionic Cells (RGCs) death gradually posing a need for neuroprotective strategies to minimize the loss of RGCs and visual field. It is recognized as a multifactorial disease, Intraocular Pressure (IOP) being the foremost risk factor. ROCK inhibitors have been probed for various possible indications, such as myocardial ischemia, hypertension, kidney diseases. Their role in neuroprotection and neuronal regeneration has been suggested to be of value in the treatment of neurological diseases, like spinal-cord injury, Alzheimer's disease and multiple sclerosis but recently Rho-associated Kinase inhibitors have been recognized as potential antiglaucoma agents.
Rho-Kinase is a serine/threonine kinase with a kinase domain which is constitutively active and is involved in the regulation of smooth muscle contraction and stress fibre formation. Two isoforms of Rho-Kinase, ROCK-I (ROCK β) and ROCK-II (ROCK α) have been identified. ROCK II plays a pathophysiological role in glaucoma and hence the inhibitors of ROCK may be beneficial to ameliorate the vision loss. These inhibitors decrease the intraocular pressure in the glaucomatous eye by increasing the aqueous humour outflow through the trabecular meshwork pathway. They also act as anti-scarring agents and hence prevent post-operative scarring after the glaucoma filtration surgery. Their major role involves axon regeneration by increasing the optic nerve blood flow which may be useful in treating the damaged optic neurons. These drugs act directly on the neurons in the central visual pathway, interrupting the RGC apoptosis and therefore serve as a novel pharmacological approach for glaucoma neuroprotection.
Based on the results of high-throughput screening, several Rho kinase inhibitors have been designed and developed comprising of diverse scaffolds exhibiting Rho kinase inhibitory activity from micromolar to subnanomolar ranges. This diversity in the scaffolds with inhibitory potential against the kinase and their SAR development will be intricated in the present review. Ripasudil is the only Rho kinase inhibitor marketed to date for the treatment of glaucoma. Another ROCK inhibitor AR-13324 has recently passed the clinical trials whereas AMA0076, K115, PG324, Y39983 and RKI-983 are still under trials. In view of this, a detailed and updated account of ROCK II inhibitors as the next generation therapeutic agents for glaucoma will be discussed in this review.
青光眼是一种进行性视神经病变，导致视力逐渐受损和视网膜神经节细胞（RGC）死亡，因此需要神经保护策略来最大程度地减少 RGC 的损失和视野丧失。它被认为是一种多因素疾病，眼内压（IOP）是首要的危险因素。ROCK 抑制剂已被用于多种可能的适应症的研究，例如心肌缺血、高血压、肾脏疾病。它们在神经保护和神经元再生中的作用被认为在治疗神经系统疾病（如脊髓损伤、阿尔茨海默病和多发性硬化症）方面具有价值，但最近 Rho 相关激酶抑制剂已被认为是有潜力的抗青光眼药物。
Rho 激酶是一种丝氨酸/苏氨酸激酶，具有一个激酶结构域，该结构域一直处于活跃状态，参与平滑肌收缩和应激纤维形成的调节。已经鉴定出两种 Rho 激酶同工型，ROCK-I（ROCKβ）和 ROCK-II（ROCKα）。ROCK II 在青光眼的病理生理学中发挥作用，因此 ROCK 的抑制剂可能有助于改善视力丧失。这些抑制剂通过增加小梁网途径的房水流出来降低青光眼眼中的眼内压。它们还作为抗瘢痕形成剂发挥作用，因此可以防止青光眼滤过手术后的术后瘢痕形成。它们的主要作用是通过增加视神经血流来促进轴突再生，这可能有助于治疗受损的视神经神经元。这些药物直接作用于中枢视觉通路中的神经元，中断 RGC 细胞凋亡，因此为青光眼神经保护提供了一种新的药理学方法。
基于高通量筛选的结果，已经设计并开发了几种 Rho 激酶抑制剂，它们包含具有从毫摩尔到亚纳摩尔范围的 Rho 激酶抑制活性的各种支架。本综述将详细讨论具有激酶抑制潜力的支架的多样性及其 SAR 发展。目前，只有 Rho 激酶抑制剂 ripasudil 被推向市场用于治疗青光眼。另一种 ROCK 抑制剂 AR-13324 最近已通过临床试验，而 AMA0076、K115、PG324、Y39983 和 RKI-983 仍在临床试验中。有鉴于此，本文将详细讨论 ROCK II 抑制剂作为治疗青光眼的下一代治疗药物。
