Novel benzodifuran analogs as potent 5-HT2A receptor agonists with ocular hypotensive activity

A series of 8-substituted benzodifuran analogs was prepared and evaluated for 5-HT2A receptor binding and activation. Several compounds containing ether and ester functionality were found to be potent agonists. Topical ocular administration of 5, 18, and 25 effectively reduced intra-ocular pressure in the hypertensive cynomolgus monkey eye in the range of 25–37%.

Graphical abstractA series of benzodifuran analogs with reduced lipophilicity were designed and synthesized as novel 5-HT2A agonists. The selected compounds 5, 18, and 25 exhibited potent and efficacious ocular hypotensive activity in cynomolgus monkey eye, affording maximum IOP reductions of 37%, 27%, and 24%, respectively, at 300 μg doses.Figure optionsDownload full-size imageDownload as PowerPoint slide