3K2F

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

Summary for 3K2F

• Entry DOI: 10.2210/pdb3k2f/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURY (II) ION, ... (5 entities in total)
• Functional Keywords: carbonic anhydrase, no-donating agent, antiglaucoma drug, sulfonamide, xray crystallography, lyase, acetylation, cytoplasm, disease mutation, metal-binding, polymorphism, zinc
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 30087.58

Authors

Temperini, C.,Cecchi, A. (deposition date: 2009-09-30, release date: 2009-11-17, Last modification date: 2023-11-01)

Primary citation

Steele, R.M.,Benedini, F.,Biondi, S.,Borghi, V.,Carzaniga, L.,Impagnatiello, F.,Miglietta, D.,Chong, W.K.,Rajapakse, R.,Cecchi, A.,Temperini, C.,Supuran, C.T.
Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma
Bioorg.Med.Chem.Lett., 19:6565-6570, 2009

PubMed Abstract: 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.

PubMed: 19854054
DOI: 10.1016/j.bmcl.2009.10.036

Experimental method

X-RAY DIFFRACTION (1.98 Å)