The Development of a New Proton‐Pump Inhibitor: The Case History of Pantoprazole

Senn‐Bilfinger, Joerg; Sturm, E.

doi:10.1002/3527608001.ch6

Cited by 11 publications

(8 citation statements)

References 21 publications

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“…The maxima of the 1D-PES for SÀ ÀCH 2 rotation (D 3 ) and for CH 2 À ÀPh rotation (D 4 ) were used as starting points for full optimization of the transition states for conformational isomerization (after releasing all constraints). All minima located on the 1D-PES maps of the structures with a planar sulfur atom were used as starting points for full optimizations of the transition states for pyramidal inversion (after releasing all constraints on D 1 , D 2 , D 3 , D 4 and the improper torsion angle CÀ ÀSÀ ÀOÀ ÀC). All the minima and transition states found at the Hatree-Fock level were upgraded to DFT B3LYP/6-31G(d) and B3LYP/6-311G(d,p).…”

Section: Methodsmentioning

confidence: 99%

“…3 Other prominent chiral sulfoxide drugs, with pharmacological activity similar to that of Omeprazole, are Pantoprazole, Lansoprazole, and Rabeprazole. 1,4 AstraZeneca has developed the chiral switch of Omeprazole to its (S)-(À)-enantiomer, as Esomeprazole magnesium. 1,3,5 Chiral switches are chiral drugs that have already been claimed, approved, and marketed as racemates or as mixtures of diastereomers but have since been redeveloped as single enantiomers.…”

Section: Introductionmentioning

confidence: 99%

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Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: A theoretical study

2007

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The pyramidal inversion mechanism of simple sulfoxides was studied, employing ab initio and DFT methods. The convergence of the geometrical and energetic parameters of H2SO and DMSO with respect to the Hamiltonian and basis set was analyzed in order to determine a computational level suitable for methyl phenyl sulfoxide (3), methyl 4-cyanophenyl sulfoxide (4), diphenyl sulfoxide (5), 4,4'-dicyanodiphenyl sulfoxide (6), benzyl methyl sulfoxide (7) and benzyl phenyl sulfoxide (8). The DFT B3LYP/6-311G(d,p) level was chosen for further calculations of larger sulfoxides. The barriers DeltaE calculated for the pyramidal inversion mechanism of sulfoxides 3-8 are in the range of 38.7-47.1 kcal/mol. These values are in good agreement with the experimental barriers for racemization via the pyramidal inversion mechanism. A resonance effect of a phenyl ring selectively stabilizes the transition state conformations, decreasing the energy barrier for pyramidal inversion by about 3 kcal/mol, compared to a similar molecule without a phenyl substituent. Introducing electron withdrawing groups (cyano) at the para positions of the phenyl ring(s) causes a further decrease of the energy barrier.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: A theoretical study

2007

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“…Pantoprazole (36) Table 5, first marketed in 1994 in Germany, obtained high selection criteria because the favorable low potential for interaction with other drugs, good solubility and very high solution stability. It became the first marketed PPI for intravenous use in critical care patients [35].…”

Section: Proton Pump Inhibitorsmentioning

confidence: 99%

Polyfluorinated Groups in Medicinal Chemistry

2015

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Introduction of novel and diverse functional groups in drug discovery is always seen with hesitancy until good activity and low toxicity characteristics are proven. The introduction of fluorine in drug-like compounds is now a well-accepted strategy in medicinal chemistry. However, polyfluoroalkyl groups, with the exception of trifluoromethyl substituents, are not well explored yet. Our aim is to show to the readers how polyfluorinated groups can be beneficial to the properties of pharmaceutically active compounds by highlighting the structure-activity relationship (SAR) studies that led to the selection of polyfluorinated moieties as key structural features. Despite the fact that the use of higher polyfluoroalkyl/aryl moieties is still in its infancy, we believe that they will soon acquire the same importance of their lower parents.

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“…1). Other prominent racemic PPI sulfoxide drugs, are Pantoprazole, Lansoprazole, and Rabeprazole 5–7. The racemic PPI inhibitor Ilaprazole (2‐[(4‐methoxy‐3‐methyl‐2‐pyridyl)methyl]sulfinyl‐5‐(1 H ‐pyrrol‐1‐yl)1 H ‐benzimidazole), CAS [172152‐36‐2] was approved by the Korean Food and Drug Administration (KFDA) in 2008.…”

Section: Introductionmentioning

confidence: 99%

Racemization of the gastrointestinal antisecretory chiral drug esomeprazole magnesium via the pyramidal inversion mechanism: A theoretical study

Marom

Agranat

2010

Chirality

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The pyramidal inversion mechanisms of the 6-methoxy and the 5-methoxy tautomers of (S)-omeprazole were studied, employing ab initio and DFT methods. The conformational space of the model molecule (S)-2-[(3-methyl-2-pyridinyl)methyl]sulfinyl-1H-benzimidazole was calculated, with respect to rotations around single bonds, at the B3LYP/6-311G(d,p) level. All of the resulting conformations were used as starting points for full optimizations of (S)-omeprazole, at B3LYP/6-31G(d), B3LYP/6-311G(d,p), B3LYP/6-311++G(d,p), B3LYP/6-311G(2df,2pd), MP2/6-31G(d), and MP2/6-311G(d,p) levels. Four distinct pathways were found for enantiomerization via the pyramidal inversion mechanism for each of the tautomers of (S)-omeprazole. Each transition state, in which the sulfur, the oxygen and the two carbon atoms connected directly to the sulfur are in one plane, connects two diastereomeric minima. The enantiomerization is completed by free rotation around the sulfur-methylene bond, and around the methylene-pyridine ring bond. The effective Gibbs' free energy barrier for racemization DeltaG(double dagger) (rac) of the two tautomers of (S)-omeprazole are 39.8 kcal/mol (5-methoxy tautomer) and 40.0 kcal/mol (6-methoxy tautomer), indicating that the enantiomers of omeprazole are stable at room temperature (in the gas phase). The 5-methoxy tautomer of (S)-omeprazole was found to be slightly more stable than the 6-methoxy tautomer, in the gas phase. The energy barrier (DeltaG(++)) for the(S,M) <=>(S,P) diastereomerization of (S)-omeprazole due to the rotation around the pyridine chiral axis was very low, 5.8 kcal/mole at B3LYP/6-311G(d,p).

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The Development of a New Proton‐Pump Inhibitor: The Case History of Pantoprazole

Cited by 11 publications

References 21 publications

Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: A theoretical study

Pyramidal inversion mechanism of simple chiral and achiral sulfoxides: A theoretical study

Polyfluorinated Groups in Medicinal Chemistry

Racemization of the gastrointestinal antisecretory chiral drug esomeprazole magnesium via the pyramidal inversion mechanism: A theoretical study

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