Synthesis and in vitro activity of various derivatives of a novel thromboxane receptor antagonist, (.+-.)-(5Z)-7-[3-endo[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-exo-yl]heptenoic acid

Abstract

Several sulfonyl derivatives (13a-t) of (+/-)-(5Z)-7-(3-endo-aminobicyclo[2.2.1]hept-2-exo-yl)heptenoic acid (VI) were synthesized via its methyl ester 10. Sulfonylation of 10 with 11a-t followed by saponification yielded 13a-t. Inhibitory concentrations (IC50) of the corresponding sodium salts 14a-t for platelet aggregation were measured with rat washed platelets (WP) and rabbit platelet-rich plasma (PRP). IC50 values of some derivatives for contraction of the rat aorta were also measured. The IC50 values for rat WP increased from 2.9 to 26 nM in the order of 14a, 14c, 14d, and 14b for derivatives with an arylsulfonyl residue, depending on the number of of intervening methylene groups. Methyl derivative 14e exhibited a higher IC50 value than n-hexyl derivative 14f. Substitution with a p-methyl, p-fluoro-, or p-chloro group in 14a retained or slightly reduced its IC50 value, while a p-n-pentyl or p-oxycarbonyl group augmented it significantly. The representative 14a suppressed (15S)-15-hydroxy-11,9-(epoxymethano)prosta-5(Z),13(E)-dienoic acid (U-46619) induced aggregation of human WP with an IC50 value of 7.7 nM, which corresponds well to the IC50 value of 3 nM obtained for each displacement by 14a of [3H]-U-46619 or (5Z,15 xi)-9 alpha, 11 alpha-(dimethylmethano)-15-hydroxy-16-(3-[125I]iodo- 4-hydroxyphenyl)-17,18,19,20-tetranor-13-aza-11a-carbathrombo-5-en oic acid [( 125I]-PTA-OH) bound to human WP. Synthesis of thromboxane A2 (TxA2) in human WP stimulated by thrombin was not inhibited by 14a at a concentration up to 10 microM. From these observations, the corresponding acid 13a (S-145) was concluded to be a potent TxA2 receptor antagonist.

Characterization and localization of thromboxane A2 receptor in human and guinea‐pig nasal mucosa using radiolabelled (+)‐S‐145

“…The biological effects of TxA 2 are mediated by the cell‐surface TxA 2 receptor (TP‐receptor) (Coleman et al , 1989), the cDNA of which has been cloned for man (Hirata et al , 1991), rats (Abe et al , 1995) and mice (Namba et al , 1992). Therefore, much effort has been directed towards the development of selective TP‐receptor antagonists (Lefer & Darius, 1987; Narisada et al , 1988; Ohtani et al , 1991), and the antagonists have been reported to be effective in a variety of experimental models including coronary thrombosis, cerebral vasospasm, ischaemia and reperfusion arrhythmias, and allergic asthma (Coleman et al , 1989; Mihara et al , 1989; Nakajima & Ueda, 1989; Arimura et al , 1992; 1994a, b; Matsuo et al , 1996).…”

Involvement of Endothelial Cyclo‐oxygenase Metabolites in Noradrenaline‐induced Contraction of Rat Coronary Artery

“…In order to examine the involvement of TXA 2 in the NA‐induced EDC mediated by COX metabolites, we used a TXA 2 synthase inhibitor (OKY‐046) and a TXA 2 receptor antagonist (S‐1452) 21,22 . The TXA 2 synthase inhibitor and TXA 2 receptor antagonist did not affect NA‐induced EDC in the rat coronary artery.…”

Effects of thromboxane A2 agonist STA2 on rapidly adapting pulmonary stretch receptors in vagotomized rabbits

“…This implies that U46619 has a direct action on TXA2 in the airways. Also, S-145 is a powerful and selective TXAa/PGH 2 receptor antagonist on platelets and vascular smooth muscle [12,13,18,23]. The fact that the increase of RAR activity produced by intraatrial injections of STA2 (0.3-3.0 p~g/kg) was greatly diminished or completely blocked by administration of S-145 (0.5 mg/kg) suggests that the STA2-induced RAR stimulation occurs as a result of the activation of TXA 2 receptors in the airways and lungs.…”