title: Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma.
abstract: Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compounds that provided a longer duration of intraocular pressure reduction in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK inhibitor, 29 (Ki=0.2nM) and demonstrated an effective and sustained IOP reduction for 24h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clinical trials for the treatment of glaucoma and ocular hypertension.
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States. Electronic address: jsturdivant@aeriepharma.com.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Sturdivant
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Royalty
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Moore
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Yingling
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Laethem
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Sherman
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Heintzelman
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Casey C
authors.initials: CC
authors.lastname: Kopczynski
authors.affiliation: Aerie Pharmaceuticals, Inc., 4301 Emperor Boulevard, Suite 400, Durham, NC 27703, United States.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: deLong
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014129:Trabecular Meshwork / Q000187:drug effects; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D001565:Benzoates; D050484:Norepinephrine Plasma Membrane Transport Proteins; D047428:Protein Kinase Inhibitors; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D015091:beta-Alanine; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C000603944:netarsudil
keywords: AR-13324; Glaucoma; Intraocular pressure (IOP); Rho kinase (ROCK); Trabecular meshwork