1-((S)-2-Aminopropyl)-1H-indazol-6-ol:  A Potent Peripherally Acting 5-HT2 Receptor Agonist with Ocular Hypotensive Activity

• Published in: Journal of medicinal chemistry Vol. 49; no. 1; pp. 318 - 328
• Main Authors: May, Jesse A, Dantanarayana, Anura P, Zinke, Paul W, McLaughlin, Marsha A, Sharif, Najam A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.01.2006; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Chemistry, Medicinal; Disease Models, Animal; Dose-Response Relationship, Drug; Eye; Haplorhini; Head Movements - drug effects; Humans; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Lasers; Life Sciences & Biomedicine; Medical sciences; Mice; Molecular Structure; Ocular Hypertension - drug therapy; Ocular Hypertension - prevention & control; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rabbits; Rats; Science & Technology; Serotonin 5-HT2 Receptor Agonists; HEAD-TWITCH RESPONSE; EPITHELIAL-CELLS; RAT; PERMEABILITY; CORTEX; BEHAVIOR; MICE; FENFLURAMINE; ANTAGONISTS; P-GLYCOPROTEIN; Antiglaucomatous agent; Agonist; Rat; Nitrogen heterocycle; Monkey; Selectivity; Eye drop; Eye; Local administration; Structure activity relation; Primates; Bicyclic compound; Aromatic compound; Chemical synthesis; Secondary amine; Human; Rodentia; In vitro; 5-HT2 Serotonine receptor; In vivo; Vertebrata; Mammalia; Animal; Phenols; Affinity; Intraocular pressure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050663x

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 α-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-HT2 receptor agonist for conducting further studies directed toward a clinical proof-of-concept study for this class of ocular hypotensive agents.