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

Abstract

The enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylpropyl)octanoic acid (1) and its pyridinyl ether analog (2) were synthesized using the highly diastereoselective method of alkylation of acyloxazolidinone. These enantiomerically pure compounds were compared with the corresponding racemic compounds 1 and 2 for their in vitro activity. Compounds 1, 1R, and 1S and 2,2S, and 2R were equipotent as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) (IC50 = 2-30 nM). Upon oral administration to guinea pigs, the enantiomers inhibited the ex vivo U 46619-induced platelet aggregation with potency similar to that of the corresponding racemic compound. This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound.

Prostanoid receptor antagonists: development strategies and therapeutic applications

“…, 1994) or combined sulotroban/daltroban moieties with ridogrel/isbogrel moieties (Figure 8), resulting in GR‐108774 (Campbell et al. , 1991b), CGS‐22652 (Bhagwat et al. , 1993) and compound 36 in Soyka et al.…”

Optical Isomerism in Drugs

“…An example is given by the antithrombotic acids 21-X and 21-Y ( Figure 18.11) [106]. Such situations are infrequent but may occur.…”