PMID- 29498522 OWN - NLM STAT- MEDLINE DCOM- 20190417 LR - 20190417 IS - 1520-4804 (Electronic) IS - 0022-2623 (Linking) VI - 61 IP - 6 DP - 2018 Mar 22 TI - 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. PG - 2552-2570 LID - 10.1021/acs.jmedchem.8b00007 [doi] AB - 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. FAU - Ehara, Takeru AU - Ehara T AUID- ORCID: 0000-0002-4889-204X AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Adams, Christopher M AU - Adams CM AUID- ORCID: 0000-0002-5246-884X AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Bevan, Doug AU - Bevan D AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Ji, Nan AU - Ji N AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Meredith, Erik L AU - Meredith EL AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Belanger, David B AU - Belanger DB AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Powers, James AU - Powers J AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Kato, Mitsunori AU - Kato M AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Solovay, Catherine AU - Solovay C AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Liu, Donglei AU - Liu D AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Capparelli, Michael AU - Capparelli M AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Bolduc, Philippe AU - Bolduc P AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Grob, Jonathan E AU - Grob JE AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Daniels, Matthew H AU - Daniels MH AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Ferrara, Luciana AU - Ferrara L AD - Ophthalmology Research , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Yang, Louis AU - Yang L AD - Ophthalmology Research , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Li, Byron AU - Li B AD - Ophthalmology Research , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Towler, Christopher S AU - Towler CS AD - Chemical and Pharmaceutical Profiling , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Stacy, Rebecca C AU - Stacy RC AD - Translational Medicine , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Prasanna, Ganesh AU - Prasanna G AD - Ophthalmology Research , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. FAU - Mogi, Muneto AU - Mogi M AD - Global Discovery Chemistry , Novartis Institutes for BioMedical Research, Inc. , Cambridge , Massachusetts 02139 , United States. LA - eng PT - Journal Article DEP - 20180302 PL - United States TA - J Med Chem JT - Journal of medicinal chemistry JID - 9716531 RN - 0 (Enzyme Activators) RN - 0 (Ophthalmic Solutions) RN - EC 4.6.1.2 (Soluble Guanylyl Cyclase) RN - H2D2X058MU (Cyclic GMP) SB - IM MH - Administration, Ophthalmic MH - Administration, Topical MH - Animals MH - CHO Cells MH - Cricetinae MH - Cricetulus MH - Cyclic GMP/biosynthesis MH - Drug Discovery MH - Enzyme Activators/administration & dosage/*chemical synthesis/*therapeutic use MH - Glaucoma/*drug therapy MH - Humans MH - Intraocular Pressure/drug effects MH - Macaca fascicularis MH - Ophthalmic Solutions MH - Oxidation-Reduction MH - Rabbits MH - Soluble Guanylyl Cyclase/*drug effects EDAT- 2018/03/03 06:00 MHDA- 2019/04/18 06:00 CRDT- 2018/03/03 06:00 PHST- 2018/03/03 06:00 [pubmed] PHST- 2019/04/18 06:00 [medline] PHST- 2018/03/03 06:00 [entrez] AID - 10.1021/acs.jmedchem.8b00007 [doi] PST - ppublish SO - J Med Chem. 2018 Mar 22;61(6):2552-2570. doi: 10.1021/acs.jmedchem.8b00007. Epub 2018 Mar 2.