Amide and alpha-keto carbonyl inhibitors of thrombin based on arginine and lysine: synthesis, stability and biological characterization.
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 alpha-keto carbonyl inhibitors having the side chain of lysine at P1. Compounds of this class are unstable by virtue of reactivity at the electrophilic carbonyl and racemization at the adjacent carbon (CH). Modifications of prototype alpha-keto-ester 8a have afforded analogs retaining nanomolar Ki. Optimal potency and stability have been realized in alpha-keto-amides 11b (Ki = 2.8 nM) and 11c (Ki = 0.25 nM).
Brady
S F
SF
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Sisko
J T
JT
Stauffer
K J
KJ
Colton
C D
CD
Qiu
H
H
Lewis
S D
SD
Ng
A S
AS
Shafer
J A
JA
Bogusky
M J
MJ
Veber
D F
DF
D000577:Amides; D000595:Amino Acid Sequence; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids; D004355:Drug Stability; D006801:Humans; D007202:Indicators and Reagents; D007659:Ketones; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014357:Trypsin / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000494:pharmacology
D000577:Amides; D000991:Antithrombins; D002264:Carboxylic Acids; D007202:Indicators and Reagents; D007659:Ketones; D009842:Oligopeptides; D014361:Trypsin Inhibitors; D014357:Trypsin; D013917:Thrombin