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
NicOx Research Institute, 20091 Bresso, Milan, Italy.
Bioorg Med Chem Lett. 2009 Dec 1;19(23):6565-70. doi: 10.1016/j.bmcl.2009.10.036. Epub 2009 Oct 13.
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.
研究了一类新型的双功能化合物，其具有与多佐胺支架相连的一氧化氮（NO）释放部分。合成了几种化合物，并在体外对重组人碳酸酐酶I、II和IV同工型评估了它们作为选择性碳酸酐酶抑制剂（CAI）的活性，结果显示它们对人碳酸酐酶II表现出不同程度的效力和选择性。CA II与化合物8形成的加合物的高分辨率X射线晶体结构证实了这类化合物对该酶具有高亲和力。通过对甲氧明预收缩的兔主动脉环的血管舒张作用评估，化合物4、6和8显示出高效且有效的NO介导特性。最后，化合物4和6在正常血压兔体内产生了显著的降低眼压（IOP）的作用，从而预示了它们在治疗高血压性青光眼方面的潜力。
