Selectivity enhancement induced by substitution of non-natural analogues of arginine and lysine in arginine-based thrombin inhibitors.
Seven non-natural analogues of arginine and lysine have been substituted in an established arginine-based thrombin inhibitor. Four of the new compounds exhibited significant thrombin inhibition (K(i)'s 0.53-3.95 microM) and were subsequently tested for selectivity against trypsin. The two best compounds gave selectivity ratios of 962 and 525 (trypsin/thrombin), improving upon the parent compound.
Kokko
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Department of Pharmaceutical Sciences, Medical University of South Carolina, PO Box 250140, 29425, Charleston, SC, USA.
Arrigoni
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Dix
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D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites / Q000502:physiology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014357:Trypsin / Q000187:drug effects*
D004791:Enzyme Inhibitors; D001120:Arginine; D014357:Trypsin; D013917:Thrombin; D008239:Lysine