Selectivity enhancement induced by substitution of non-natural analogues of arginine and lysine in arginine-based thrombin inhibitors

K P Kokko; C E Arrigoni; T A Dix

doi:10.1016/s0960-894x(01)00328-6

Selectivity enhancement induced by substitution of non-natural analogues of arginine and lysine in arginine-based thrombin inhibitors

Bioorg Med Chem Lett. 2001 Jul 23;11(14):1947-50. doi: 10.1016/s0960-894x(01)00328-6.

Authors

K P Kokko¹, C E Arrigoni, T A Dix

Affiliation

¹ Department of Pharmaceutical Sciences, Medical University of South Carolina, PO Box 250140, 29425, Charleston, SC, USA.

PMID: 11459667
DOI: 10.1016/s0960-894x(01)00328-6

Abstract

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.

MeSH terms

Arginine / analogs & derivatives*
Arginine / chemical synthesis
Arginine / pharmacology*
Binding Sites / physiology
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology
Humans
Lysine / analogs & derivatives*
Lysine / chemical synthesis
Lysine / pharmacology*
Sensitivity and Specificity
Thrombin / antagonists & inhibitors*
Trypsin / drug effects*

Substances

Enzyme Inhibitors
Arginine
Trypsin
Thrombin
Lysine