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Titolo:
6,6-DISUBSTITUTED HEX-5-ENOIC ACID-DERIVATIVES AS COMBINED THROMBOXANE A(2) RECEPTOR ANTAGONISTS AND SYNTHETASE INHIBITORS
Autore:
SOYKA R; HECKEL A; NICKL J; EISERT W; MULLER TH; WEISENBERGER H;
Indirizzi:
DR KARL THOMAE GMBH,DEPT RES,BIRKENDORFER STR 65 D-88397 BIBERACH GERMANY DR KARL THOMAE GMBH,DEPT CHEM BIBERACH GERMANY DR KARL THOMAE GMBH,DEPT PHARMACOL BIBERACH GERMANY DR KARL THOMAE GMBH,DEPT BIOCHEM BIBERACH GERMANY
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 1, volume: 37, anno: 1994,
pagine: 26 - 39
SICI:
0022-2623(1994)37:1<26:6HAACT>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
SYNTHASE INHIBITION; PROSTAGLANDIN ENDOPEROXIDES; PHARMACOLOGICAL EVALUATION; HUMAN-PLATELETS; ONE MOLECULE; BLOCKADE; RIDOGREL; PROSTACYCLIN; INVITRO; ASPIRIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
46
Recensione:
Indirizzi per estratti:
Citazione:
R. Soyka et al., "6,6-DISUBSTITUTED HEX-5-ENOIC ACID-DERIVATIVES AS COMBINED THROMBOXANE A(2) RECEPTOR ANTAGONISTS AND SYNTHETASE INHIBITORS", Journal of medicinal chemistry, 37(1), 1994, pp. 26-39

Abstract

A series of omega-disubstituted alkenoic acid derivatives were designed and synthesized as antithrombotic inhibitors of thromboxane A(2) synthetase and thromboxane A(2) receptor antagonists. Hexenoic acid derivatives with a 3-pyridyl group and a 4-(2-benzenesulfonamidoethyl)phenyl substituent were found to be optimal with regard to the dual mode of action. The most potent compound, fonyl)amino)ethyl)phenyl)-6-(3-pyridyl)hex-5-enoic acid (36), inhibits thromboxane A(2) synthetase in gel-filtered human platelets with an IC50 value of 4.5 +/- 0.5 nM (n = 4),whereas an inhibitory effect on cyclooxygenase is seen only at a much higher concentration (IC50: 240 mu M). Radioligand-binding studies with [H-3]SQ 29,548 in washed human platelets revealed that 36 blocks the prostaglandin H-2/thromboxane A(2) receptor with an IC50 Of 19 +/- 5 nM (n = 5) and is therefore 85-fold more potent than another combined thromboxane A(2) synthetase inhibitor/ receptor antagonist, Ridogrel(4). Compound 36 inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an EC(50) of 1 mu M (Ridogrel: 16 mu M) and 100 nM, respectively, and was selected for further development.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/07/20 alle ore 21:15:36