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Titolo:
Inhibitory effects of newly synthesized active center-directed trypsin-like serine protease inhibitors on the complement system
Autore:
Ueda, N; Midorikawa, A; Ino, Y; Oda, M; Nakamura, K; Suzuki, S; Kurumi, M;
Indirizzi:
Torii Pharmaceut Co Ltd, Res Lab, Chiba 2670056, Japan Torii Pharmaceut CoLtd Chiba Japan 2670056 es Lab, Chiba 2670056, Japan
Titolo Testata:
INFLAMMATION RESEARCH
fascicolo: 1, volume: 49, anno: 2000,
pagine: 42 - 46
SICI:
1023-3830(200001)49:1<42:IEONSA>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
SYNTHETIC INHIBITORS; KALLIKREIN; ESTERASE; THROMBIN; INVITRO; PLASMIN; INVIVO;
Keywords:
FUT-175 (nafamostat mesilate); complement serine protease inhibitor complement-mediated hemolysis; Forssman systemic shock;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
19
Recensione:
Indirizzi per estratti:
Indirizzo: Ueda, N Japan Tabacco Inc, Cent Pharmaceut Res Inst, 1-1 Murasaki Cho, Takatsuki, Osaka 5691125, Japan Japan Tabacco Inc 1-1 Murasaki Cho Takatsuki Osaka Japan 5691125 n
Citazione:
N. Ueda et al., "Inhibitory effects of newly synthesized active center-directed trypsin-like serine protease inhibitors on the complement system", INFLAMM RES, 49(1), 2000, pp. 42-46

Abstract

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 C1 (r) over bar and C1 (s) over bar with IC50s of 1.7 x 10(-6) and 3.2 x 10(-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 C1 (r) over bar and the complement-mediated hemolysis inhigh-diluted serum with higher potency than FUT-175, The inhibitory activity of compound 6 in hemolysis was weakened in low diluted serum. Compound 7had 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/01/20 alle ore 01:19:24