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Abstract #78973 Published in IGR 20-1
Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit
Spadoni G; Bedini A; Furiassi L; Mari M; Mor M; Scalvini L; Lodola A; Ghidini A; Lucini V; Dugnani S; Scaglione F; Piomelli D; Jung KM; Supuran CT; Lucarini L; Durante M; Sgambellone S; Masini E; Rivara SJournal of Medicinal Chemistry 2018; 61: 7902-7916
Activation of melatonin receptors and inhibition of fatty acid amide hydrolase (FAAH) have both shown potential benefits for the treatment of glaucoma. To exploit the combination of these biological activities in single therapeutic agents, we designed dual-acting compounds sharing the pharmacophore elements required for the two targets, in search for balanced potencies as MT/MT agonists and FAAH inhibitors. In particular, the N-anilinoethylamide scaffold, previously developed for melatonergic ligands, was decorated at meta position with a polymethylene linker bound to an O-arylcarbamate group, substituted according to known structure-activity relationships for FAAH inhibition. For the most active series, the N-anilinoethylamide portion was also replaced with the indole scaffold of melatonin. O-Biphenyl-3-ylcarbamate derivatives were characterized by remarkable and balanced activity at both targets, in the nanomolar range for compound 29. Topical administration reduced elevated intraocular pressure in rabbits, with a longer action and improved efficacy compared to the reference compounds melatonin and URB597.
Dipartimento di Scienze Biomolecolari , Università degli Studi di Urbino "Carlo Bo" , Piazza Rinascimento 6 , I-61029 Urbino , Italy.
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