| Autor: |
Li C; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Zhu M; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Liu S; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Zhang J; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Ye H; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Zhang C; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Ji D; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Tang H; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Zhang Y; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Wu J; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Huang Z; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.; School of Pharmacy, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi 830054, China. |
| Abstrakt: |
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. |
