Synthesis of novel nitric oxide (NO)-releasing esters of timolol

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 10; pp. 2785 - 2788
• Main Authors: Chiroli, Valerio, Batugo, Minerva R., Biondi, Stefano, Bonfanti, Annalisa, Brambilla, Stefania, Gale, David C., Li, Lin, Miglietta, Daniela, Nicoli, Fabio, Prasanna, Ganesh A., Ronchetti, Daniela, Vernier, William F., Chong, Wesley K.M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-05-2009; Elsevier
• Subjects: Adrenergic beta-Antagonists - metabolism; Beta-blocker; Biological and medical sciences; Cardiovascular system; Drug Stability; Esters - chemistry; Esters - metabolism; Eye; Guanylate Cyclase - antagonists & inhibitors; Guanylate Cyclase - metabolism; Medical sciences; Nitric Oxide - metabolism; Nitric oxide conjugate; Pharmacology. Drug treatments; Timolol; Timolol - chemistry; Trigger; Vasodilator agents. Cerebral vasodilators; Vasorelaxation assay; Beta-blocker; Vasodilator agent; Chemical stability; Rabbit; Lagomorpha; Nitric oxide conjugate; In vitro; Biological activity; β-Adrenergic receptor; Ester; Vertebrata; Nitric oxide donor; Vasorelaxation assay; Mammalia; Trigger; Animal; Nitric oxide; Organic nitrate; Aorta; Antagonist; Conjugated compound; Chemical synthesis; Timolol; Beta blocking agent
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.03.111

A novel class of timolol derivatives with nitric oxide (NO)-donating moieties achieved chemical stability yet under physiologically relevant conditions released timolol and NO. Hindered esters
A were designed and synthesized, whose ‘triggered’ release relied on enzymatic hydrolysis of the nitrate ester in
A to
B, that in turn cyclized to liberate timolol.