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

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Steele RM, Benedini F, Biondi S, Borghi V, Carzaniga L, Impagnatiello F, Miglietta D, Chong WK, Rajapakse R, Cecchi A, Temperini C, Supuran CT

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

Bioorg Med Chem Lett. 2009 Dec 1;19(23):6565-70. doi: 10.1016/j.bmcl.2009.10.036. Epub 2009 Oct 13.

PubMed ID

19854054 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Dorzolamide	Carbonic anhydrase 1	Ki (nM)	50000	N/A	N/A	Details
Dorzolamide	Carbonic anhydrase 2	Ki (nM)	9	N/A	N/A	Details
Dorzolamide	Carbonic anhydrase 4	Ki (nM)	43	N/A	N/A	Details