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 Chemjournal_title
Journal of medicinal chemistryauthors
May JA,Sharif NA,McLaughlin MA,Chen HH,Severns BS,Kelly CR,Holt WF,Young R,Glennon RA,Hellberg MR,Dean TRdoi
10.1021/acs.jmedchem.5b00857subject
Has Abstractpub_date
2015-11-25 00:00:00pages
8818-33issue
22eissn
0022-2623issn
1520-4804journal_volume
58pub_type
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