Lactam-conformationally restricted analogs of N alpha-arylsulfonyl arginine amide: design, synthesis and inhibitory activity toward thrombin and related enzymes.
Three new lactam-conformationally restricted arginine derivatives, 1-butyl-3-(6,7-dimethoxy-2-naphthylsulfonyl)-3-(3-guanidinoprop yl)-substituted gamma-, delta-, and epsilon-lactams (2-4), were synthesized on the basis of backbone modification of the lead structure, 6,7-dimethoxy-2-naphthylsulfonylarginine n-butylmethylamide (1). We tested these compounds for inhibitory activity toward thrombin and other trypsin-like enzymes (trypsin, factor Xa, plasmin, and kallikrein). All the compounds synthesized (1-4) potently inhibited thrombin with IC50 values of 0.75, 0.70, 0.92, and 3.2 microM, respectively; they inhibited thrombin over 40-fold more effectively than the other enzymes tested. The gamma-lactam (2) with the most profound inhibitory activity toward thrombin was a reversible inhibitor with a Ki of 0.26 microM. Compound 2 also showed better thrombin selectivity than the lead compound (1). The lactam-conformational restriction of arylsulfonylarginine amides, especially gamma-lactam, has thus proved to be a useful device for the improvement of antithrombotic activity.
Okayama
T
T
Research Institute, Fuji Chemical Industries, Ltd, Toyama, Japan.
Seki
S
S
Ito
H
H
Takeshima
T
T
Hagiwara
M
M
Morikawa
T
T
D001120:Arginine / Q000031:analogs & derivatives*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013917:Thrombin / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007769:Lactams; D001120:Arginine; D013917:Thrombin