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

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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-11, Vol.58 (22), p.8818-8833
Main Authors: May, Jesse A, Sharif, Najam A, McLaughlin, Marsha A, Chen, Hwang-Hsing, Severns, Bryon S, Kelly, Curtis R, Holt, William F, Young, Richard, Glennon, Richard A, Hellberg, Mark R, Dean, Thomas R
Format: Article
Language:English
Subjects:
Administration, Topical
Animals
Anti-Inflammatory Agents, Non-Steroidal - administration & dosage
Anti-Inflammatory Agents, Non-Steroidal - therapeutic use
Benzophenones - administration & dosage
Benzophenones - therapeutic use
Bromobenzenes - administration & dosage
Bromobenzenes - therapeutic use
Cornea - metabolism
Glaucoma - drug therapy
HT29 Cells
Humans
In Vitro Techniques
Indazoles - adverse effects
Indazoles - chemical synthesis
Indazoles - therapeutic use
Indicators and Reagents
Intraocular Pressure - drug effects
Macaca fascicularis
Ocular Hypertension - drug therapy
Permeability
Rats
Receptors, Adrenergic, alpha - metabolism
Receptors, Serotonin - metabolism
Serotonin 5-HT2 Receptor Agonists - adverse effects
Serotonin 5-HT2 Receptor Agonists - therapeutic use
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00857