title: 1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity.
abstract: Serotonin 5-HT(2) receptor agonists have been identified as a potential new class of agents for the treatment of ocular hypertension and glaucoma. The initially reported tryptamine analogues displayed either poor solution stability, potent central nervous system activity, or both of these undesirable characteristics and were unacceptable for clinical evaluation. A series of 1-(2-aminopropyl)-1H-indazole analogues was synthesized and evaluated for their suitability for consideration as clinical candidates. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol (9) was identified as a peripherally acting potent 5-HT(2) receptor agonist (EC(50) = 42.7 nM, E(max) = 89%) with high selectivity for the 5-HT(2) receptors relative to other serotonergic receptor subtypes and other families of receptors and has significantly greater solution stability than alpha-methyl-5-hydroxytryptamine. Additionally, 9 potently lowers intraocular pressure in conscious ocular hypertensive monkeys (-13 mmHg, 33%); this reduction appears to be through a local rather than a centrally mediated effect. Compound 9 appears to be an excellent 5-HT(2) receptor agonist for conducting further studies directed toward a clinical proof-of-concept study for this class of ocular hypotensive agents.
authors.affiliation: Ophthalmology Discovery Research, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, Texas 76134, USA. jesse.may@alconlabs.com
authors.forename: Jesse A
authors.initials: JA
authors.lastname: May
authors.forename: Anura P
authors.initials: AP
authors.lastname: Dantanarayana
authors.forename: Paul W
authors.initials: PW
authors.lastname: Zinke
authors.forename: Marsha A
authors.initials: MA
authors.lastname: McLaughlin
authors.forename: Najam A
authors.initials: NA
authors.lastname: Sharif
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D019416:Head Movements / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007834:Lasers; D051379:Mice; D015394:Molecular Structure; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000517:prevention & control; D011817:Rabbits; D051381:Rats; D058826:Serotonin 5-HT2 Receptor Agonists
chemical_list: C507821:1-(2-aminopropyl)-1H-indazol-6-ol; D007191:Indazoles; D058826:Serotonin 5-HT2 Receptor Agonists