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Abstract #25390 Published in IGR 12-1
Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma
Steele R M; Benedini F; Biondi S; Borghi V; Carzaniga L; Impagnatiello F; Miglietta D; Chong W K M; Rajapakse R; Cecchi ABioorganic and Medicinal Chemistry Letters 2009; 19: 6565-6570
Novel bi-functional compounds with a nitric oxide (NO)-releasing moiety bound to a dorzolamide scaffold were investigated. Several compounds were synthesized and their activity as selective carbonic anhydrase inhibitors (CAI) evaluated in vitro on recombinant hCA type I, II and IV enzyme isoforms where they showed different degrees of potency and selectivity to hCA II. A high resolution X-ray crystal structure for the CA II adduct with 8 confirmed the high affinity of this class of compounds for the enzyme. Compounds 4, 6, and 8 showed highly potent and efficacious NO-mediated properties as assessed by their vascular relaxant effect on methoxamine-precontracted rabbit aortic rings. Finally, compounds 4 and 6 exerted potent intraocular pressure (IOP) lowering effects in vivo in normotensive rabbits thereby anticipating their potential for the treatment of hypertensive glaucoma.
R.M. Steele. NicOx Research Institute, Via Ariosto 21, 20091 Bresso, Milan, Italy. steele@nicox.it
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
