Development of Nitric Oxide-Donating Netarsudil Derivatives as a Synergistic Therapy for Glaucoma with Reduced Ocular Irritation

Based on the synergistic therapeutic effect of nitric
oxide (NO)
and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a
series of NO-donating Netarsudil derivatives were designed, synthesized,
and their activities in vitro and in vivo were evaluated. Among them,
(S)-10e released an appropriate amount
of NO in aqueous humor in vitro and displayed potent ROCK inhibition.
Topical administration of (S)-10e significantly
lowered intraocular pressure in an acute ocular hypertension rabbit
model and protected retinal ganglion cells in a magnetic microbead
occlusion mouse model. A metabolism investigation revealed that (S)-10e released 7a, a metabolite
after NO releasing, and 13, an active metabolite of (S)-Netarsudil, in rabbit eyes. Notably, introducing an NO
donor moiety attenuated ROCK inhibition-induced ocular irritation
in an sGC-independent manner, suggesting that the attenuated conjunctival
hyperemia effect of (S)-10e is related
to the NO-induced protein S-nitrosation of phosphodiesterase 3A (PDE3A).
Overall, (S)-10e is a promising candidate
for glaucoma treatment.

基于一氧化氮（NO）与Rho相关蛋白激酶（ROCK）抑制剂协同治疗青光眼的疗效，设计、合成了系列NO供体Netarsudil衍生物，并对其体外及体内活性进行了评估。其中，（S）-10e在体外水溶性介质中释放了适量的NO，并表现出显著的ROCK抑制活性。在急性眼压升高兔模型中，局部应用（S）-10e显著降低了眼内压，并在磁性微球阻塞小鼠模型中保护了视网膜神经节细胞。代谢研究揭示了（S）-10e在兔眼中释放了7a，即NO释放后的代谢产物，以及13，即（S）-Netarsudil的活性代谢物。值得注意的是，引入NO供体基团以sGC非依赖性方式减轻了ROCK抑制引起的眼部刺激，这表明（S）-10e减轻结膜充血效应与NO诱导的磷酸二酯酶3A（PDE3A）蛋白质S-硝基化作用有关。总体而言，（S）-10e是治疗青光眼的潜在候选药物。