Inhibitory effects of newly synthesized active center-directed trypsin-like serine protease inhibitors on the complement system.
OBJECTIVE
To obtain a synthetic anti-complement inhibitor which has stronger activity than FUT-175 (nafamostat mesilate), as a synthetic ester derivative containing amidino and guanidino groups.


METHODS
We synthesized several modified compounds of FUT-175. The anti-complement activities were measured using synthetic substrates and complement-mediated hemolysis in vitro. The anti-complement activity in vivo was evaluated via Forssman systemic shock in guinea pigs.


RESULTS
FUT-175 inhibited C1r and C1s with IC50s of 1.7x10(-6) and 3.2x10(-7) M, respectively. Inhibitory activities were decreased by substitution of the amidino group with a hydrogen atom (compound 2), but not the guanidino group with a hydrogen atom (compound 3). Compound 6, in which the benzene ring of compound 3 was substituted with a furan ring, inhibited C1r and the complement-mediated hemolysis in high-diluted serum with higher potency than FUT-175. The inhibitory activity of compound 6 in hemolysis was weakened in low diluted serum. Compound 7 had a guanidino group inserted into compound 6; however, Compound 7 strongly inhibited hemolysis even in low-diluted serum, and suppressed Forssman systemic shock more potently than both FUT-175 and compound 6.


CONCLUSIONS
These data suggest that the 2-furylcarboxylic acid derivatives have a strong potential for inhibiting the activities of the complement, and the guanidino group was required to retain high inhibitory activities in vivo, and compound 7 is a hopeful anti-complement agent.
Ueda
N
N
Research Laboratory, Torii Pharmaceutical Co. Ltd., Chiba-shi, Japan.
Midorikawa
A
A
Ino
Y
Y
Oda
M
M
Nakamura
K
K
Suzuki
S
S
Kurumi
M
M
D000818:Animals; D001550:Benzamidines; D003174:Complement C1 Inactivator Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D015923:Complement C1r / Q000502:physiology; D003173:Complement C1s / Q000502:physiology; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006461:Hemolysis; D008297:Male; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D012769:Shock / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014361:Trypsin Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D001550:Benzamidines; D003174:Complement C1 Inactivator Proteins; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D015923:Complement C1r; D003173:Complement C1s; C032855:nafamostat