Amide and α-keto carbonyl inhibitors of thrombin based on arginine and lysine: Synthesis, stability and biological characterization

• Published in: Bioorganic & medicinal chemistry Vol. 3; no. 8; pp. 1063 - 1078
• Main Authors: Brady, Stephen F., Sisko, John T., Stauffer, Kenneth J., Colton, Christiana D., Qiu, Howard, Lewis, Sidney D., Ng, Assunta S., Shafer, Jules A., Bogusky, Michael J., Veber, Daniel F., Nutt, Ruth F.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-08-1995
• Subjects: Amides; Amino Acid Sequence; Antithrombins - chemical synthesis; Antithrombins - chemistry; Antithrombins - pharmacology; Carboxylic Acids; Drug Stability; Humans; Indicators and Reagents; Ketones; Kinetics; Molecular Sequence Data; Molecular Structure; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Spectrometry, Mass, Fast Atom Bombardment; Structure-Activity Relationship; Thrombin - antagonists & inhibitors; Trypsin - metabolism; Trypsin Inhibitors - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/0968-0896(95)00105-P

We report structure-activity investigations in a series of tripeptide amide inhibitors of thrombin, and the development of a series of highly potent active site directed α-keto carbonyl inhibitors having the side chain of lysine at P
1. Compounds of this class are unstable by virtue of reactivity at the electrophilic carbonyl and racemization at the adjacent carbon (CH). Modifications of prototype α-keto-ester
8a have afforded analogs retaining nanomolar
K
i
. Optimal potency and stability have been realized in α-keto-amides
11b
(K
i = 2.8
nM) and
11c (K
i = 0.25
nM)
Extrapolation from a set of thrombin-inhibitory amides, H-P
3-P
2-Arg-NH
2, has afforded the prototype inhibitor
I with the aminobutyl side chain of lysine replacing the guanidinopropyl side chain of arginine. Selected modifications of
I have led to analogs (
II-IV exhibiting nanomolar K
i (thrombin) Factors which affect chemical stability nad racemization in this class have been evaluated. Optimal structures have been realized in keto amides
I and
II.