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.

S-145, (+/-)-(5Z)-7-[3-endo-[(phenylsulfonyl)amino]bicyclo[2.2.1] 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. For 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 (rho) 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 [log(1/IC50)] showed parabolic correlations with the n value, though the rho 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 (rho = 83%) and S-145 (rho = 89%), the IC50 values of 41 and 2.9 nM for rat WP were 10 and 141 times lower than that of 6 (rho = 52%), respectively. In these compounds, which form the 12-membered ring, the inhibitory potencies increase as the rho value increases.