Structure-activity studies of cyclic ketone inhibitors of the serine protease plasmin: design, synthesis, and biological activity.
Three series of cyclic ketone inhibitors were synthesized and evaluated against the serine protease plasmin. Peptide inhibitors that incorporated 3-oxotetrahydrofuran and 3-oxotetrahydrothiophene 1,1-dioxide groups had the highest activities. Alkylamino substituents, which were designed to bind in the S1 subsite of plasmin, were attached to the inhibitors. Compounds 5c and 5g, which incorporated 6-aminohexyl substituents, were found to be optimal and demonstrated IC(50) values in the low micromolar range. Incorporating conformationally constrained peptide segments into the inhibitors did not improve their activities.
Xue
Fengtian
F
Department of Chemistry, Brown University, 324 Brook Street, Box H, Providence, RI 02912, USA.
Seto
Christopher T
CT
D015195:Drug Design; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D005343:Fibrinolytic Agents; D007659:Ketones; D015842:Serine Proteinase Inhibitors; D005341:Fibrinolysin