title: Ocular Hypotensive Response in Nonhuman Primates of (8R)-1-[(2S)-2-Aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol a Selective 5-HT2 Receptor Agonist.
abstract: Recently, it has been reported that 5-HT2 receptor agonists effectively reduce intraocular pressure (IOP) in a nonhuman primate model of glaucoma. Although 1-[(2S)-2-aminopropyl]indazol-6-ol (AL-34662) was shown to have good efficacy in this nonhuman primate model of ocular hypertension as well as a desirable physicochemical and permeability profile, subsequently identified cardiovascular side effects in multiple species precluded further clinical evaluation of this compound. Herein, we report selected structural modifications that resulted in the identification of (8R)-1-[(2S)-2-aminopropyl]-8,9-dihydro-7H-pyrano[2,3-g]indazol-8-ol (13), which displayed an acceptable profile to support advancement for further preclinical evaluation as a candidate for proof-of-concept studies in humans.
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: May
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Najam A
authors.initials: NA
authors.lastname: Sharif
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Marsha A
authors.initials: MA
authors.lastname: McLaughlin
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Hwang-Hsing
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Bryon S
authors.initials: BS
authors.lastname: Severns
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Kelly
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: William F
authors.initials: WF
authors.lastname: Holt
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Box 980540, Richmond, Virginia 23298, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Young
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Box 980540, Richmond, Virginia 23298, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellberg
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd. , 6201 South Freeway, Fort Worth, Texas 76134, United States.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Dean
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D001577:Benzophenones / Q000008:administration & dosage / Q000627:therapeutic use; D001969:Bromobenzenes / Q000008:administration & dosage / Q000627:therapeutic use; D003315:Cornea / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy; D019073:HT29 Cells; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use*; D007202:Indicators and Reagents; D007429:Intraocular Pressure / Q000187:drug effects; D008252:Macaca fascicularis; D009798:Ocular Hypertension / Q000188:drug therapy*; D010539:Permeability; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: C520575:1-(2-aminopropyl)-1H-indazole-6-ol; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001577:Benzophenones; D001969:Bromobenzenes; D007191:Indazoles; D007202:Indicators and Reagents; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D058826:Serotonin 5-HT2 Receptor Agonists; C053083:bromfenac