98105-45-4Relevant articles and documents
New potential renin inhibitors with dipeptide replacements in the molecule
Winiecka, Iwona,Dudkiewicz-Wilczynska, Jadwiga,Roman, Iza,Paruszewski, Ryszard
scheme or table, p. 367 - 374 (2011/08/04)
A series of eight non-peptidic potential renin inhibitors have been designed and synthesized. All of them contain dipeptide replacement: (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) in their molecules. Four among them comprise two additional analogs of dipeptide: (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) and (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta). All of the synthesized compounds contain also hydrophobic portions to receive a moderate lipophilicity of the molecules. Inhibitory activity of the compounds was measured in vitro by HPLC determination of Leu-Val-Tyr-Ser released from the N-acetyltetradecapeptide substrate by renin in the presence of the inhibitor. Asp-α(OEt)-(S,S)-ACHPA-εAhx-Iaa (23) shows inhibitory activity (7%) at the concentration of 1.0 × 10-2 M. The other synthesized compounds show no inhibitory activity up to this concentration.
Syntheses and biological activities of renin inhibitors containing statine analogues
Nishi,Saito,Nagahori,Kataoka,Morisawa,Yabe,Sakurai,Higashida,Shoji,Matsushita,Iijima,Ohizumi,Koike
, p. 103 - 109 (2007/10/02)
-
1,2,4-Triazolopyrazine Derivatives with Human Renin Inhibitory Activity. 1. Synthesis and Biological Properties of Alkyl Alcohol and Statine Derivatives
Roberts, David A.,Bradbury, Robert H.,Brown, David,Faull, Alan,Griffiths, David,et al.
, p. 2326 - 2334 (2007/10/02)
A series of 1,2,4-triazolopyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) transition-state mimetics, have been prepared.Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-pyrazin-3-yl>-3-(3-pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen.Compounds 12m, 12o, and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration.On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion.The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.
