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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, an sGC activator specifically designed for topical ocular delivery as a therapy for glaucoma

Ehara, Takeru and Adams, Christopher and Bevan Jr, Doug and Ji, Nan and Meredith, Erik and Belanger, David and Powers, James and Kato, Mitsunori and Solovay, Catherine and Liu, Donglei and Capparelli, Michael and Bolduc, Philippe and Grob, Jonathan and Daniels, Matthew and Ferrara, Luciana and Yang, Louis and Towler, Christopher and Li, Byron and Stacy, Rebecca and Prasanna, Ganesh and Mogi, Muneto (2018) 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, an sGC activator specifically designed for topical ocular delivery as a therapy for glaucoma. Journal of medicinal chemistry. ISSN DOI: 10.1021/acs.jmedchem.8b00007

Abstract

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 intra ocular pressure over 24h after a single topical ocular drop, and has been selected for clinical evaluation.

Item Type: Article
Date Deposited: 16 Mar 2018 00:45
Last Modified: 16 Mar 2018 00:45
URI: https://oak.novartis.com/id/eprint/34659

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