Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1995; 74(04): 1107-1112
DOI: 10.1055/s-0038-1649889

Original Article

Coagulation

Schattauer GmbH Stuttgart

Inhibition of Thrombin by Peptides Containing Lysyl-α-Keto Carbonyl Derivatives

Sidney D Lewis

,

Assunta S Ng

¹The Department of Biological Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Elizabeth A Lyle

³The Department of Pharmacology, Merck Research Laboratories, West Point, PA, USA

,

Michael J Mellott

³The Department of Pharmacology, Merck Research Laboratories, West Point, PA, USA

,

Sandra D Appleby

³The Department of Pharmacology, Merck Research Laboratories, West Point, PA, USA

,

Stephen F Brady

²The Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Kenneth J Stauffer

²The Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA

,

John T Sisko

²The Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Shi-Shan Mao

¹The Department of Biological Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Daniel F Veber

²The Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Ruth F Nutt

²The Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Joseph J Lynch

³The Department of Pharmacology, Merck Research Laboratories, West Point, PA, USA

,

Jacquelynn J Cook

³The Department of Pharmacology, Merck Research Laboratories, West Point, PA, USA

,

Stephen J Gardll

¹The Department of Biological Chemistry, Merck Research Laboratories, West Point, PA, USA

,

Jules A Shafer

¹The Department of Biological Chemistry, Merck Research Laboratories, West Point, PA, USA

› Author Affiliations

Summary

Several H-N-Me-D-Phe-Pro-Lysyl-α-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 α-keto carbonyl compounds appeared to occur via a one-step reversible reaction. The α-keto carbonyl inhibitors bound thrombin with a second order rate constant (k, 1–4 μM^-1s^-1) that was 10–100-fold slower than that expected for a diffusion-controlled reaction. Certain α-kelo earbonyl 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 α-keto carbonyl thrombin inhibitors suggests the possibility that α-keto amide containing thrombin inhibitors may have utility as orally-active antithrombotic agents.

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