113949-52-3Relevant articles and documents
An usual rearrangement of Zofenopril, a new ACE inhibitor drug: Mass spectrometric and conformational studies
Cartoni, Antonella,Altamura, Maria,Animati, Fabio,Balacco, Giuseppe,Cosi, Riccardo,Ettorre, Alessandro,Madami, Andrea,Triolo, Antonio
, p. 1258 - 1265 (2002)
Zofenopril (1) is a new ACE inhibitor, used in therapy for hypertension and post-myocardial infarction. The protonated quasi-molecular ion (m/z 430) of 1, obtained under positive electrospray ionization conditions, loses a benzoic acid molecule (m/z 308), which in turn decomposes via loss of CO (m/z 280) when low-energy collisional-induced dissociation (CID) and in-source experiments are performed. This rearrangement is the main fragmentation process and can be observed both in-source and in the product ion tandem mass spectra, using either an ion trap or a triple quadrupole instrument. Other known diastereoisomers of 1, an impurity with an acetyl in the place of the benzoyl group (2) and an impurity with two propanoyl chains in series (3), give the same rearrangement. On the other hand, the mass spectra of the methyl ester (4) and an impurity with two proline moieties (5) do not show this unusual fragmentation. Time-resolved CID spectra of 1 show that the rearrangement occurs after about 2 ms, a time scale comparable to those of the other non-rearrangement cleavages. These experiments suggest a conformation in the gas phase for 1 in which the benzoyl group is close to the hydroxyl of the carboxylic acid group, from which the rearrangement could readily occur. Since compounds 4 and 5 do not show the same behaviour, the presence of a carboxylic acid in the proline ring seems to play a crucial role in the rearrangement, probably due to an intramolecular hydrogen bond. To confirm this hypothesis, deuterium exchanges in mass spectrometric experiments and a conformational analysis via computational methods were performed. Copyright
Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines
Krapcho,Turk,Cushman,Powell,DeForrest,Spitzmiller,Karanewsky,Duggan,Rovnvak,Schwartz,Natarajan,Godfrey,Ryono,Neubeck,Atwa,Petrillo Jr.
, p. 1148 - 1160 (2007/10/02)
Analogues of captopril, enalaprilat, and the phosphinic acid [[hydroxy(4-phenylbutyl)phosphinyl]acetyl)-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
