Single Enantiomer Versus Racemate: Chiral Distinction in the Proton Pump Inhibitors Omeprazole and Esomeprazole

Abstract

Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral-switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6-311G(d,p), the 6-methoxy∙∙∙6-methoxy and 5-methoxy∙∙∙5-methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG(298,(RS-SS))) between the cyclic C2-(S,S)- and Ci-(R,S)-dimers with two intermolecular hydrogen bonds are 3.8, 1.9 (with BSSE counterpoise correction), and -6.9 (with D3 dispersion and BSSE counterpoise corrections) kJ/mol. Adding water as an implicit solvent (polarized continuum model [PCM] model) resulted in a chiral distinction energy of -3.3 kJ/mol, indicating a reversal of the order of the relative stabilities of C2-(S,S)- and Ci-(R,S)-dimers. The chiral distinction free energies between the corresponding (less stable) C1-dimers with one intermolecular hydrogen bond are -9.3, -5.8 (with BSSE CC), 17.6 (D3 + BSSE CC), and -3.2 (H2O) kJ/mol. The results highlight the contention that omeprazole is not just a superposition of its enantiomer constituents. They are consistent with the pharmacological evidence of enantiomer-enantiomer interactions in omeprazole versus esomeprazole and the differences between the drugs omeprazole and esomeprazole magnesium and support the lodged application for regulatory supplementary protection certificate (SPC) exclusivity for the esomeprazole-related combination drug Vimovo.

First Synthesis and Characterization of Stereoisomers of Choleretic Drug Dihydroxydibutylether

“…For example, esomeprazole is the S-enantiomer of omeprazole. [10] Both are proton pump inhibitors that are widely used worldwide. Similarly, levocetirizine is the levoisomer of cetirizine, which came to the market in 2001, showing a very good antihistamine activity.…”

Continuous Flow Synthesis of Esomeprazole via Asymmetric Sulfoxidation

“…Optically active sulfoxides have been widely used as chiral intermediates, auxiliaries, and chiral ligands. A portion of chiral sulfoxides have also represented an important class of pharmaceuticals and drug intermediates, especially as the proton pump inhibitors (PPIs) blockbuster drug esomeprazole. − Esomeprazole, the S-enantiomer of omeprazole, is one of the best-selling PPIs, which provides better acid control than current comparable drugs and has a favorable pharmacokinetic profile compared with its racemic omeprazole. − The key step in the synthesis of esomeprazole is the enantioselective sulfoxidation of ufiprazole. Several methods have been developed for the process with oxaziridines; , bio- or enzymatic catalysis; , and chiral metal complex catalysts, such as titanium, ,− vanadium, , manganese, , and iron , systems (Scheme A).…”