Renin Inhibitors. II. Synthesis and Structure-Activity Relationships of N-Terminus Modified Inhibitors Containing a Homostatine Analogue

抄録

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatine analogue, (2RS, 4S, 5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS, 4S, 5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7-methyloctanamie (20) has an IC₅₀ of 0.5 nM against human plasma renin and the oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.