Department of Medicinal Chemistry & Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612-7231, USA.
Future Med Chem. 2013 Aug;5(12):1451-68. doi: 10.4155/fmc.13.111.
Nitric oxide (NO)/solube GC (sGC)/cGMP signaling is important for modulating synaptic transmission and plasticity in the hippocampus and cerebral cortex, which are critical for learning and memory. Physiological concentrations of NO also elicit anti-apoptotic/prosurvival effects against various neurotoxic challenges and brain insults through multiple mechanisms. Depression of the NO/sGC pathway is a feature of Alzheimer's disease (AD), attributed to amyloid-β neuropathology, and altered expression and activity of NOS, sGC and PDE enzymes. Different classes of NO-releasing hybrid drugs, including nomethiazoles, NO-NSAIDs and NO-acetylcholinesterase inhibitors were designed to deliver low concentrations of exogenous NO to the CNS while targeting other underlying disease mechanisms, such as excitotoxicity, neuro-inflammation and acetylcholine deficiency, respectively. Incorporating a NO-donating moiety may also reduce gastrointestinal and liver toxicity of the parent drugs. Progress has also been made in targeting downstream sGC and PDE enzymes. The PDE9 inhibitor PF-04447943 has completed Phase II clinical trials for AD. The search for effective NO-donating hybrid drugs, CNS-targeting sGC stimulators/activators and selective PDE inhibitors is an important goal for pharmacotherapy that manipulates NO biochemical pathways involved in cognitive function and neuroprotection. Rigorous preclinical validation of target engagement, and optimization of pharmacokinetic and toxicity profiles are likely to advance more drug candidates into clinical trials for mild cognitive impairment and early stage AD.
一氧化氮（NO）/可溶性鸟苷酸环化酶（sGC）/环鸟苷酸（cGMP）信号通路对于调节海马体和大脑皮层中的突触传递和可塑性非常重要，而这些对于学习和记忆至关重要。生理浓度的一氧化氮还通过多种机制对各种神经毒性挑战和脑损伤产生抗凋亡/存活作用。阿尔茨海默病（AD）中 NO/sGC 途径的抑制归因于淀粉样蛋白-β神经病理学，以及 NOS、sGC 和 PDE 酶的表达和活性改变。不同类别的一氧化氮释放混合药物，包括硝甲噻唑、NO-非甾体抗炎药和 NO-乙酰胆碱酯酶抑制剂，旨在向中枢神经系统输送低浓度的外源性一氧化氮，同时针对其他潜在的疾病机制，如兴奋性毒性、神经炎症和乙酰胆碱缺乏症。引入一氧化氮供体部分也可能降低母体药物的胃肠道和肝脏毒性。针对下游 sGC 和 PDE 酶的研究也取得了进展。PDE9 抑制剂 PF-04447943 已完成 AD 的 II 期临床试验。寻找有效的一氧化氮释放混合药物、中枢神经系统靶向 sGC 刺激剂/激活剂和选择性 PDE 抑制剂是一种重要的治疗目标，旨在调节与认知功能和神经保护相关的一氧化氮生化途径。对靶标结合的严格临床前验证，以及对药代动力学和毒性特征的优化，可能会使更多的候选药物进入轻度认知障碍和早期 AD 的临床试验。
