Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines

Abstract

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.

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

“…To this end, we screened different phosphinic peptide libraries, using a systematic approach previously described (14,15). Such phosphinic peptides were chosen because they are highly potent inhibitors of several zinc-metallopeptidases (14)(15)(16)(17)(18) and are good analogues of the substrate in the transition-state for this class of enzyme (19). They were screened on wild-type ACE and ACE mutants in which either the N-or the C-domain of ACE had been inactivated, as reported before (3).…”

Cardiovascular Drugs

“…Fosinopril (25) and spirapril (32) both have proline derivatives as C-terminal amino acid. The trans-4-cyclohexylproline in fosinopril can be prepared from the native trans-4-hydroxyproline as follows [75]:…”

Molecular tools for cell and systems biology

“…Most work so far has been done on ion chelators (Grynkiewicz et al, 1985;Tsien, 1981), nucleotides (Friis and Bundgaard, 1996;Peyrottes et al, 2004;Schultz, 2003;Schultz et al, 1994Schultz et al, , 1993, inositol phosphates (Li et al, 1998;Rudolf et al, 2003;Vajanaphanich et al, 1994), phosphoinositides (Dinkel et al, 2001;Jiang et al, 1998), and other lipid derivatives . In addition, some small molecule sensor molecules (Wichmann et al, 2006;Zlokarnik et al, 1998) but also some commercial drugs rely on this technique (Krapcho et al, 1988;Starret et al, 1994;von Daehne et al, 1970).…”