The Discovery of (<i>S</i>)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1<i>H</i>-inden-4-yl)pyridin-2-yl)-5-methyl-1<i>H</i>-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma
作者:Takeru Ehara、Christopher M. Adams、Doug Bevan、Nan Ji、Erik L. Meredith、David B. Belanger、James Powers、Mitsunori Kato、Catherine Solovay、Donglei Liu、Michael Capparelli、Philippe Bolduc、Jonathan E. Grob、Matthew H. Daniels、Luciana Ferrara、Louis Yang、Byron Li、Christopher S. Towler、Rebecca C. Stacy、Ganesh Prasanna、Muneto Mogi
DOI:10.1021/acs.jmedchem.8b00007
日期:2018.3.22
Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing
可溶性鸟苷酸环化酶(sGC)是一氧化氮(NO)的内源性受体,与多种与氧化应激有关的疾病有关。在病理性氧化环境中,sGC的血红素基团可被氧化而变得对NO无响应,从而导致催化cGMP产生的能力下降。最近,功能异常的sGC / NO / cGMP途径与青光眼相关的眼内压升高有关。在这里,我们描述了专门设计用于局部眼部给药的分子的发现,该分子可以激活氧化的sGC,恢复催化cGMP产生的能力。这些努力最终导致了化合物(+)-23的鉴定,可在单次局部滴眼后24小时内强烈降低眼内压升高的食蟹猴模型中的眼内压,已被选择用于临床评估。