Stereoselective synthesis and thromboxane A2 (TXA2) receptor antagonistic activity of optically active phenol derivatives.
Enantiomers of four potent nonprostanoid thromboxane A2 (TXA2) receptor antagonists, (+/-)-7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (1-4), were synthesized stereoselectively by direct ortho-alkylation of phenols under modified Mitsunobu conditions. The reaction of 5 eq of phenols (6a-c) with 1 eq of (S)- or (R)-methyl 7-(4-fluorophenyl)-7-hydroxyheptanoate ((S)- or (R)-7) afforded ortho-alkylated phenol derivatives (6a-c) enantioselectively in 33 to 42% chemical yield and 90 to 93% ee. In these compounds, the (R)-enantiomers (1-4) exhibited potent TXA2 receptor antagonistic activity and the (S)-isomer (3) was much less active. In particular, compound (R)-3 strongly inhibited U-46619-induced human platelet aggregation (IC50 = 48 nM), and also showed a very potent inhibitory effect with a minimum effective dose (MED) of 0.3 mg/kg (p.o.) on U-46619-induced bronchoconstriction in guinea pigs.
Fukumoto
S
S
Pharmaceutical Research Laboratories II, Takeda Chemical Industries, Ltd., Osaka, Japan.
Terashita
Z
Z
Ashida
Y
Y
Terao
S
S
Shiraishi
M
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001993:Bronchodilator Agents; D010636:Phenols; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid