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.

Abstract:

: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.

journal_name

J Med Chem

authors

May JA,Sharif NA,McLaughlin MA,Chen HH,Severns BS,Kelly CR,Holt WF,Young R,Glennon RA,Hellberg MR,Dean TR

doi

10.1021/acs.jmedchem.5b00857

subject

Has Abstract

pub_date

2015-11-25 00:00:00

pages

8818-33

issue

22

eissn

0022-2623

issn

1520-4804

journal_volume

58

pub_type

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