1-((S)-2-aminopropyl)-1H-indazol-6-ol:: A potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity

Serotonin 5-HT2 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-HT2 receptor agonist (EC50 = 42.7 nM, E-max = 89%) with high selectivity for the 5-HT2 receptors relative to other serotonergic receptor subtypes and other families of receptors and has significantly greater solution stability than alpha-methyl-5-hydroxy-tryptamine. 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-HT2 receptor agonist for conducting further studies directed toward a clinical proof-of-concept study for this class of ocular hypotensive agents.