FTIR Spectral Study of Intramolecular Hydrogen Bonding in Thromboxane A2 Receptor Antagonist S-145 and Related Compounds. 3. Conformation and Activity of S-145 Analogues

Article abstract of DOI:10.1021/jm00110a020

S-145, (+/-)-(5Z)-7-<3-endo<(phenylsulfonyl)amino>bicyclo<2.2.1>hept-2-exo-yl>heptenoic acid, its chain analogues HO2C(CH2)nNHSO2Ph (n=3-8,10, and 11) 1-8, and (5Z)-9-(phenylsulfonyl)aminonon-5-enoic acid (9) were synthesized in order to elucidate the dependence of the conformation in solution and of the pharmacological activity on the side-chain length.Their FTIR spectra were measured in dilute CCl4 solution.Tor these compounds, intramolecular hydrogen bonds similar to those observed for S-145 were found between the carboxyl and sulfonamido groups.A linear relationship was also found between the percentage (ρ) of the intramolecular hydrogen-bonded molecules and the n value.Compounds 1-9 were examined in vitro for inhibitory concentrations (IC50) against U-46619- and collagen-induced aggregations for rabbit and rat washed platelets (WP), respectively, and U-46619-induced contraction for rat aorta.Three kinds of TXA₂ receptor antagonistic potencies showed parabolic correlations with the n value, though the ρ value was in direct proportion to the n value.The log (1/IC50) values for 6 (n=8), which forms a 12-membered ring similar to the one observed for S-145, were found to be maximal values in 1-8 and were comparable to those for BM-13177.In compounds 9 (ρ = 83percent) and S-145 (ρ = 89percent), the IC50 values of 41 and 2.9 nM for rat WP were 10 and 141 times lower than that of 6 (ρ = 52percent), respectively.In these compounds, which form the 12-membered ring, the inhibitory potencies increase as the ρ value increases.