title: Structure-activity studies of cyclic ketone inhibitors of the serine protease plasmin: design, synthesis, and biological activity.
abstract: 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.
authors.affiliation: Department of Chemistry, Brown University, 324 Brook Street, Box H, Providence, RI 02912, USA.
authors.forename: Fengtian
authors.initials: F
authors.lastname: Xue
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Seto
mesh_terms: 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
chemical_list: D005343:Fibrinolytic Agents; D007659:Ketones; D015842:Serine Proteinase Inhibitors; D005341:Fibrinolysin