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
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- 作者：Jesse A. May ; Najam A. Sharif ; Marsha A. McLaughlin ; Hwang-Hsing Chen ; Bryon S. Severns ; Curtis R. Kelly ; William F. Holt ; Richard Young ; Richard A. Glennon ; Mark R. Hellberg ; Thomas R. Dean
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：November 25, 2015
- 年：2015
- 卷：58
- 期：22
- 页码：8818-8833
- 全文大小：501K
- ISSN：1520-4804
文摘
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.