Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: stereochemistry and tautomerism.
A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3-C2-S10-O11), D2 (C2-S10-C12-C13), and D3 (S10-C12-C13-N14) and two methoxy rotations defined by D4 (C6-C5-O8-C9) and D5 (C16-C17-O19-C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer.
Caner
Hava
H
Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Cheeseman
James R
JR
Agranat
Israel
I
D004064:Digestive System / Q000187:drug effects* / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000737:chemistry*; D008968:Molecular Conformation; D009853:Omeprazole / Q000737:chemistry*; D013237:Stereoisomerism; D013816:Thermodynamics
D005765:Gastrointestinal Agents; D009853:Omeprazole