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.

Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma / R. M. Steele;F. Benedini;S. Biondi;V. Borghi;L. Carzaniga;F. Impagnatiello;D. Miglietta;W. K. M;R. Rajapakse;A. Cecchi;C. Temperini;C. T. Supuran. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - STAMPA. - 19:(2009), pp. 6565-6570. [10.1016/j.bmcl.2009.10.036]

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

SUPURAN, CLAUDIU TRANDAFIR
2009

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.
2009
19
6565
6570
R. M. Steele;F. Benedini;S. Biondi;V. Borghi;L. Carzaniga;F. Impagnatiello;D. Miglietta;W. K. M;R. Rajapakse;A. Cecchi;C. Temperini;C. T. ...espandi
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/776182
Citazioni
  • ???jsp.display-item.citation.pmc??? 11
  • Scopus 58
  • ???jsp.display-item.citation.isi??? 54
social impact