Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids

Abstract

A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.

Development of Dual-Acting Agents for Thromboxane Receptor Antagonism and Thromboxane Synthase Inhibition. 3. Synthesis and Biological Activities of Oxazolecarboxamide-Substituted ω-Phenyl-ω-(3-pyridyl)alkenoic Acid Derivatives and Related Compounds

“…Though both the oxazoles and the oxazoline intermediates were discovered as novel and potent dual TRA/TSIs, we opted to pursue the oxazole series for further SAR study rather than the oxazolines because of the greater chemical stability and somewhat better TRA activities observed in the oxazole series . The effect of acid side-chain length indicates that there is an optimal distance for each binding element . The hairpin conformation hypothesis proposed by Andersen et al states that thromboxane receptor binding requires a prostaglandin conformation with a U-shaped or approximately parallel arrangement of the α- and ω-side chains.…”

“…A simple approach to design compounds with dual action for TRA/TSI in a single chemical entity has been to incorporate the binding elements of each activity into a “hybrid” structure, connecting each binding element by a certain “spacer” allowing an appropriate distance .…”

“…It is important to realize, however, that this “hybridization” should introduce the desired pharmacological property in a new molecule without the introduction of unwanted side effects such as agonist activity and protein binding which could be induced by the new physicochemical nature of the compound designed . It is known that sulfonamide-derived compounds have a tendency to exhibit agonist activity . During the course of our TRA/TSI research program, we therefore sought a different binding element from a sulfonamide for TRA activity and discovered a new class of phenyloxazole derivatives 4 .…”

Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 5. Synthesis and evaluation of enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylalkyl)octanoic acid

“…The 0 See ref 7 for methodology. 6 Time at which blood samples were taken out to measure platelet aggregability.c Concentration ratio = EC50 for drug/ECso for control. enantiomers of 1 and 2 were also found to be similar in their bioavailability in an ex vivo model in guinea pigs.…”

“…3 We have undertaken a program to develop compounds which possess both TxRA and TxSI activities. [4][5][6][7] In a previous publication7 we have described the structureactivity relationships (SAR) and in vitro/in vivo profile of 1 and 2 which behave as TxRA and TxSI. The presence of one chiral center in both 1 and 2 suggested the preparation and testing of their enantiomers.…”