Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Su T,Naughton MA,Smyth MS,Rose JW,Arfsten AE,McCowan JR,Jakubowski JA,Wyss VL,Ruterbories KJ,Sall DJ,Scarborough RMdoi
10.1021/jm9704863subject
Has Abstractpub_date
1997-12-19 00:00:00pages
4308-18issue
26eissn
0022-2623issn
1520-4804pii
jm9704863journal_volume
40pub_type
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