Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines.
New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin.
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Stefan
S
Hinkes
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
André
A
Wuttke
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Sebastian M
SM
Saupe
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Teodora
T
Ivanova
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Sebastian
S
Wagner
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Anna
A
Knörlein
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Andreas
A
Heine
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Gerhard
G
Klebe
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
Torsten
T
Steinmetzer
D000933:Antifibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001550:Benzamidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000933:Antifibrinolytic Agents; D001550:Benzamidines; D001596:Benzylamines; D005341:Fibrinolysin