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 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.
NicOx Research Institute, 20091 Bresso, Milan, Italy. steele@nicox.it
Rebecca M
RM
Steele
Francesca
F
Benedini
Stefano
S
Biondi
Valentina
V
Borghi
Laura
L
Carzaniga
Francesco
F
Impagnatiello
Daniela
D
Miglietta
Wesley K M
WK
Chong
Ranjan
R
Rajapakse
Alessandro
A
Cecchi
Claudia
C
Temperini
Claudiu T
CT
Supuran
D000818:Animals; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D008958:Models, Molecular; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D009569:Nitric Oxide; C062765:dorzolamide; D024402:Carbonic Anhydrase II