Synthesis and in vitro activity of stereoisomers of a novel thromboxane receptor antagonist, (+-)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo [2.2.1]hept-2-exo-yl]heptenoic acid.
Three stereoisomers of S-145 (1) with variations at the side-chain junctions were synthesized. Endo-cis isomer 10 and N-exo-trans isomer 18 were obtained via the common intermediate 5 having an endo-fused ring structure. Exo-cis isomer 28 was prepared via exo-fused azetidino compound 21. Inhibitory concentrations (IC50) of the sodium salts newly obtained for platelet aggregation were measured using washed rat platelets (WP) and human platelet-rich plasma (PRP). The IC50 values of these compounds for contraction of the rat aorta were also measured. Compound 1 of N-endo-trans structure and N-exo-trans isomer 18 exhibited more potent inhibitory activity than cis-isomers 10 and 28 against responses induced by TXA2-related substances for rat WP and rat thoracic aorta. However, these compounds exhibited almost comparable inhibitory activity for human PRP.
Ohtani
M
M
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Narisada
M
M
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D005229:Fatty Acids, Monounsaturated; D010975:Platelet Aggregation Inhibitors; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C056566:S 145; D013928:Thromboxane A2