- 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
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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.
- Ehara, Takeru,Adams, Christopher M.,Bevan, Doug,Ji, Nan,Meredith, Erik L.,Belanger, David B.,Powers, James,Kato, Mitsunori,Solovay, Catherine,Liu, Donglei,Capparelli, Michael,Bolduc, Philippe,Grob, Jonathan E.,Daniels, Matthew H.,Ferrara, Luciana,Yang, Louis,Li, Byron,Towler, Christopher S.,Stacy, Rebecca C.,Prasanna, Ganesh,Mogi, Muneto
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p. 2552 - 2570
(2018/03/26)
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- CYCLOHEXEN-1-YL-PYRIDIN-2-YL-1H-PYRAZOLE-4-CARBOXYLIC ACID DERIVATIVES AND THE USE THEREOF AS SOLUBLE GUANYLATE CYCLASE ACTIVATORS
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The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacolo
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Page/Page column 54
(2016/02/28)
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- Rh2(II)-catalyzed ester migration to afford 3 H-indoles from trisubstituted styryl azides
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Rh2(II)-Complexes trigger the formation of 3H-indoles from ortho-alkenyl substituted aryl azides. This reaction occurs through a 4π-electron-5-atom electrocyclization of the rhodium N-aryl nitrene followed by a [1,2]-migration to afford only 3H-indoles. The selectivity of the migration is dependent on the identity of the β-styryl substituent.
- Kong, Chen,Driver, Tom G.
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supporting information
p. 802 - 805
(2015/04/27)
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- Total synthesis and comparative analysis of orlistat, valilactone, and a transposed orlistat derivative: Inhibitors of fatty acid synthase
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Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the α-side chain. Versatile strategies for modifying the δ-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.
- Ma, Gil,Zancanella, Manuel,Oyola, Yatsandra,Richardson, Robyn D.,Smith, Jeffrey W.,Romo, Daniel
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p. 4497 - 4500
(2007/10/03)
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