当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
The Discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-02 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00007 Takeru Ehara 1 , Christopher M. Adams 1 , Doug Bevan 1 , Nan Ji 1 , Erik L. Meredith 1 , David B. Belanger 1 , James Powers 1 , Mitsunori Kato 1 , Catherine Solovay 1 , Donglei Liu 1 , Michael Capparelli 1 , Philippe Bolduc 1 , Jonathan E. Grob 1 , Matthew H. Daniels 1 , Luciana Ferrara 2 , Louis Yang 2 , Byron Li 2 , Christopher S. Towler 3 , Rebecca C. Stacy 4 , Ganesh Prasanna 2 , Muneto Mogi 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-02 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00007 Takeru Ehara 1 , Christopher M. Adams 1 , Doug Bevan 1 , Nan Ji 1 , Erik L. Meredith 1 , David B. Belanger 1 , James Powers 1 , Mitsunori Kato 1 , Catherine Solovay 1 , Donglei Liu 1 , Michael Capparelli 1 , Philippe Bolduc 1 , Jonathan E. Grob 1 , Matthew H. Daniels 1 , Luciana Ferrara 2 , Louis Yang 2 , Byron Li 2 , Christopher S. Towler 3 , Rebecca C. Stacy 4 , Ganesh Prasanna 2 , Muneto Mogi 1
Affiliation
|
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 to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.
中文翻译：
（S）-1-（6-（3-（（4-（1-（环丙烷羰基）哌啶-4-基）-2-甲基苯基）氨基）-2,3-二氢-1 H-茚满-的发现4-yl）pyridin-2-yl）-5-methyl-1 H-吡唑-4-羧酸，一种可溶性鸟苷酸环化酶激活剂，专门设计用于局部眼部递送以治疗青光眼
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。
更新日期：2018-03-02
中文翻译：
（S）-1-（6-（3-（（4-（1-（环丙烷羰基）哌啶-4-基）-2-甲基苯基）氨基）-2,3-二氢-1 H-茚满-的发现4-yl）pyridin-2-yl）-5-methyl-1 H-吡唑-4-羧酸，一种可溶性鸟苷酸环化酶激活剂，专门设计用于局部眼部递送以治疗青光眼
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。
京公网安备 11010802027423号