169319-62-4Relevant academic research and scientific papers
Efficient large scale preparation of neutral endopeptidase/ angiotensin-converting enzyme dual inhibitor CGS30440
Johnson, Erik P.,Cantrell Jr., William R.,Jenson, Todd M.,Miller, Scott A.,Parker, David J.,Reel, Noela M.,Sylvester, Leo G.,Szendroi, Robert J.,Vargas, Kevin J.,Xu, Jean,Carlson, John A.
, p. 238 - 244 (2013/09/08)
The development and piloting of a potential manufacturing process for ACE/NEP dual inhibitor CGS30440 is described. The synthesis proceeds sequentially from 1-aminocyclopentanecarboxylic acid via N-protection, peptide coupling with L-tyrosine ethyl ester, O-methylation of N-protected [(1-amino-1-cyclopentyl)carbonyl]-L-tyrosine ethyl ester, N-deprotection, peptide coupling of [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-L-tyrosine ethyl ester with D-2-bromo-3-methylbutyric acid, and final displacement of bromide with thioacetate. This approach is superior to shorter Discovery routes based upon final peptide coupling of L-2-(acetylthio)-3-methylbutanoic acid to [(1-amino-1-cyclopentyl)carbonyl]-O-methyl-L-tyrosine ethyl ester.
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.
