Inhibition of thrombin by peptides containing Lysyl-alpha-keto carbonyl derivatives
Lewis, S.D.; Ng, A.S.; Lyle, E.A.; Mellott, M.J.; Appleby, S.D.; Brady, S.F.; Stauffer, K.J.; Sisko, J.T.; Mao, S.S.; Veber, D.F.
Thrombosis and Haemostasis 74(4): 1107-1112
1995
ISSN/ISBN: 0340-6245 PMID: 8560421 Document Number: 442050
Several H-N-Me-D-Phe-Pro-Lysyl-alpha-keto carbonyl derivatives were shown to be potent thrombin inhibitors (K-i 0.2 to 27 nM). The inhibitory potencies of these compounds toward tissue plasminogen activator, plasmin and factor Xa were minimal: however, substantial cross-reactivity versus trypsin was observed (K-i values from 0.5 to 1500 nM). Inhibition of thrombin by alpha-keto carbonyl compounds appeared to occur via a one-step reversible reaction. The times -keto carbonyl inhibitors bound thrombin with a second order rate constant (k-1 1-4 mu-M-1s-1) that was 10-100-fold slower than that expected for a diffusion-controlled reaction. Certain alpha-keto carbonyl inhibitors were as potent (on a weight basis) as hirudin when evaluated in a rat arterial thrombosis model. The modest oral bioavailability (10-19%) in rats demonstrated for three of the alpha-keto carbonyl thrombin inhibitors suggests the possibility that alpha-keto amide containing thrombin inhibitors may have utility as orally-active antithrombotic agents.