169319-42-0Relevant articles and documents
Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin- converting enzyme and neutral endopeptidase
Fink, Cynthia A.,Carlson, J. Eric,McTaggart, Patricia A.,Qiao, Ying,Webb, Randy,Chatelain, Ricardo,Jeng, Arco Y.,Trapani, Angelo J.
, p. 3158 - 3168 (2007/10/03)
Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I-converting enzyme (ACE, EC 2.4.15.1), have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. We have previously reported that compound 2 (N-[[1-[(2(S)-mercapto-3-methyl-1-oxobutyl)amino]-1- cyclopentyl]carbonyl]-L-tyrosine) was a potent dual inhibitor in vitro (IC50(ACE) = 7.0 nM, IC50(NEP) = 1.5 nM) (Fink et al. J. Med. Chem. 1995, 38, 5023-5030). This compound was found to have oral activity; however, its duration of effect was short. A series of thioacetate carboxylic acid ester analogs of compound 2 was prepared. Modifications were also made to the tyrosine phenol. These compounds were evaluated for their ability to inhibit plasma ACE activity when administered orally to conscious normotensive rats. Most of the compounds prepared were found to be orally active with longer durations of effect than compound 2. Compound 38 (N[[1-[(2(S)-(acetylthio)- 3-methyl-1-oxobutyl)amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosine ethyl ester), administered at 11.7 mg/kg po, was found to be more efficacious than captopril at 10 mg/kg po. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. Compound 38 was found to lower blood pressure in the aorta-ligated rat and the spontaneously hypertensive rat when administered orally. The synthesis and biological activity of these dual inhibitors are discussed.
New α-thiol dipeptide dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase EC 3.4.24.11
Fink,Qiao,Berry,Sakane,Ghai,Trapani
, p. 5023 - 5030 (2007/10/03)
Dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP, EC 3.4.24.11) and angiotensin-I converting enzyme, have been the focus of much clinical interest for the treatment of hypertension and congestive heart failure. A novel series of α-thio dipeptides containing central cyclic non-natural amino acids were prepared and were evaluated for their ability to inhibit these two metallopeptidases in vitro and in vivo. Most of these compounds were found to be excellent dual inhibitors of ACE and NEP in vitro and several were also found to inhibit angiotensin-I (AI) pressor response in conscious rats when given by intravenous administration. Compound 6n, one of our most potent dual inhibitors in vitro, was found to be more efficacious than captopril in the AI pressor experiment when administered orally to conscious rats. This compound was also found to inhibit plasma NEP activity following oral administration to conscious rats and was more efficacious than acetorphan. The structure-activity relationships and biological activity of these dual inhibitors will be discussed.
