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
| Autor: | Mark R. Hellberg, Bryon S. Severns, William F. Holt, Richard Young, Richard A. Glennon, Thomas R. Dean, Najam A. Sharif, Hwang-Hsing Chen, Curtis R. Kelly, Marsha A. McLaughlin, Jesse A. May |
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| Rok vydání: | 2015 |
| Předmět: |
Agonist
Intraocular pressure medicine.medical_specialty Indazoles medicine.drug_class Administration Topical Ocular hypertension Glaucoma Pharmacology In Vitro Techniques Permeability Cornea Benzophenones Structure-Activity Relationship Internal medicine Drug Discovery medicine Structure–activity relationship Animals Humans Receptor Intraocular Pressure Chemistry 5-HT2 receptor Anti-Inflammatory Agents Non-Steroidal Receptors Adrenergic alpha Multiple species medicine.disease Rats Macaca fascicularis Endocrinology Receptors Serotonin Molecular Medicine Indicators and Reagents Ocular Hypertension HT29 Cells Serotonin 5-HT2 Receptor Agonists Bromobenzenes |
| Zdroj: | Journal of medicinal chemistry. 58(22) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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