title: Inhibition of thrombin by peptides containing Lysyl-alpha-keto carbonyl derivatives.
abstract: Several H-N-Me-D-Phe-Pro-Lysyl-alpha-keto carbonyl derivatives were shown to be potent thrombin inhibitors (Ki 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 (Ki 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 alpha-keto carbonyl inhibitors bound thrombin with a second order rate constant (k1 1-4 microM-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.
authors.affiliation: Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Lewis
authors.forename: A S
authors.initials: AS
authors.lastname: Ng
authors.forename: E A
authors.initials: EA
authors.lastname: Lyle
authors.forename: M J
authors.initials: MJ
authors.lastname: Mellott
authors.forename: S D
authors.initials: SD
authors.lastname: Appleby
authors.forename: S F
authors.initials: SF
authors.lastname: Brady
authors.forename: K J
authors.initials: KJ
authors.lastname: Stauffer
authors.forename: J T
authors.initials: JT
authors.lastname: Sisko
authors.forename: S S
authors.initials: SS
authors.lastname: Mao
authors.forename: D F
authors.initials: DF
authors.lastname: Veber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage*; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000378:metabolism*; D005296:Ferrous Compounds; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage* / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014361:Trypsin Inhibitors / Q000008:administration & dosage
chemical_list: D000991:Antithrombins; D005296:Ferrous Compounds; D010455:Peptides; D014361:Trypsin Inhibitors; D013917:Thrombin; D005341:Fibrinolysin