Hajduk P J, Boyd S, Nettesheim D, Nienaber V, Severin J, Smith R, Davidson D, Rockway T, Fesik S W
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Med Chem. 2000 Oct 19;43(21):3862-6. doi: 10.1021/jm0002228.
Using an NMR-based screen, a novel class of urokinase inhibitors were identified that contain a 2-aminobenzimidazole moiety. The inhibitory potency of this family of inhibitors is similar to that of inhibitors containing a guanidine or amidine group. However, unlike previously described guanidino- or amidino-based inhibitors which have pK(a) values greater than 9.0, urokinase inhibitors containing a 2-aminobenzimidazole have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved pharmacokinetic properties which could increase the bioavailability of inhibitors which contain this moiety. A crystal structure of one of the lead inhibitors, 2-amino-5-hydroxybenzimidazole, complexed with urokinase reveals the electrostatic and hydrophobic interactions that stabilize complex formation and suggests nearby subsites that may be accessed to increase the potency of this new series of urokinase inhibitors.
通过基于核磁共振的筛选，鉴定出了一类新型的尿激酶抑制剂，其含有2-氨基苯并咪唑部分。该类抑制剂的抑制效力与含有胍基或脒基的抑制剂相似。然而，与先前描述的pK(a)值大于9.0的基于胍基或脒基的抑制剂不同，含有2-氨基苯并咪唑的尿激酶抑制剂的pK(a)值为7.5。因此，2-氨基苯并咪唑可能具有改善的药代动力学性质，这可能会提高含有该部分的抑制剂的生物利用度。先导抑制剂之一2-氨基-5-羟基苯并咪唑与尿激酶复合的晶体结构揭示了稳定复合物形成的静电和疏水相互作用，并暗示了附近可能可利用的亚位点，以提高这一系列新型尿激酶抑制剂的效力。
