Su T, Naughton M A, Smyth M S, Rose J W, Arfsten A E, McCowan J R, Jakubowski J A, Wyss V L, Ruterbories K J, Sall D J, Scarborough R M
COR Therapeutics, Inc., South San Francisco, California 94080, USA.
J Med Chem. 1997 Dec 19;40(26):4308-18. doi: 10.1021/jm9704863.
A series of highly potent and specific fibrinogen receptor antagonists have been discovered and optimized through structural modification of the novel amidinoindole and benzofuran compounds, I and II. Systematic linker optimization afforded the amidinobenzofuran-containing inhibitor 29, which displayed an IC50 value of 250 nM in platelet aggregation assays. Attempts to enhance activity by modification of the beta-position of the beta-alanyl carboxylate group of 29 had only a modest effect on inhibitory activity in aggregation assays. Analogues prepared to enhance the activity by conformational restriction were also found to be equally or less potent. In contrast, modification at the alpha-position of the beta-alanyl carboxylate group resulted in the identification of extremely potent and novel amidinobenzofuran-containing derivatives 46-49. Reexamination of 5,6-bicyclic aromatic nucleus led to the further identification of amidinoindole- and amidinoindazole-containing derivatives 53-55. These analogues, 46-49 and 53-55, exhibited potent in vitro activity with IC50 values of 25-65 nM in platelet aggregation assays and an IC50 value of 2 nM in fibrinogen binding assays and demonstrated a selectivity of > 50,000-fold for GPIIb-IIIa versus the most closely related integrin, the vitronectin receptor, alpha v beta 3.
通过对新型脒基吲哚和苯并呋喃化合物I和II进行结构修饰，已发现并优化了一系列高效且特异的纤维蛋白原受体拮抗剂。通过系统的连接子优化得到了含脒基苯并呋喃的抑制剂29，其在血小板聚集试验中的IC50值为250 nM。试图通过修饰29的β-丙氨酸羧酸酯基团的β-位来增强活性，在聚集试验中对抑制活性的影响不大。为通过构象限制增强活性而制备的类似物也被发现效力相当或更低。相比之下，在β-丙氨酸羧酸酯基团的α-位进行修饰，导致鉴定出了极具效力的新型含脒基苯并呋喃的衍生物46 - 49。对5,6-双环芳核的重新研究导致进一步鉴定出了含脒基吲哚和脒基吲唑的衍生物53 - 55。这些类似物，即46 - 49和53 - 55，在血小板聚集试验中表现出高效的体外活性，IC50值为25 - 65 nM，在纤维蛋白原结合试验中的IC50值为2 nM，并且相对于最密切相关的整合素——玻连蛋白受体αvβ3，对GPIIb - IIIa表现出>50,000倍的选择性。
