2. Academic Validation
  3. The Discovery of ( S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1 H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma

The Discovery of ( S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1 H-inden-4-yl)pyridin-2-yl)-5-methyl-1 H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma

  • J Med Chem. 2018 Mar 22;61(6):2552-2570. 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
Affiliations

Affiliations

  • 1 Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States.
  • 2 Ophthalmology Research , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States.
  • 3 Chemical and Pharmaceutical Profiling , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States.
  • 4 Translational Medicine , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States.
PMID: 29498522 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 intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.

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