Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma

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 wh...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-12, Vol.19 (23), p.6565-6570
Main Authors: Steele, Rebecca M., Benedini, Francesca, Biondi, Stefano, Borghi, Valentina, Carzaniga, Laura, Impagnatiello, Francesco, Miglietta, Daniela, Chong, Wesley K.M., Rajapakse, Ranjan, Cecchi, Alessandro, Temperini, Claudia, Supuran, Claudiu T.
Format: Article
Language:English
Subjects:
Animals
Antiglaucoma drug
Biological and medical sciences
Carbonic anhydrase
Carbonic Anhydrase II - antagonists & inhibitors
Carbonic Anhydrase Inhibitors - chemical synthesis
Carbonic Anhydrase Inhibitors - chemistry
Carbonic Anhydrase Inhibitors - therapeutic use
Crystallography, X-Ray
Dorzolamide
Drug Discovery
Eye
Glaucoma, Open-Angle - drug therapy
Medical sciences
Models, Molecular
Molecular Structure
Nitric Oxide - chemistry
NO-donating agent
Pharmacology. Drug treatments
Rabbits
Structure-Activity Relationship
Sulfonamide
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - therapeutic use
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - therapeutic use
X-ray crystallography
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Description
Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.10.036