Novel renin inhibitors containing (2S,3S,5S)-2-amino-1-cyclohexyl-6-methyl-3,5-heptanediol fragment as a transition-state mimic at the P1-P1' cleavage site

Y Yamada; K Ando; Y Ikemoto; H Tada; E Shirakawa; E Inagaki; S Shibata; I Nakamura; Y Hayashi; K Ikegami; I Uchida

doi:10.1248/cpb.45.1631

Novel renin inhibitors containing (2S,3S,5S)-2-amino-1-cyclohexyl-6-methyl-3,5-heptanediol fragment as a transition-state mimic at the P1-P1' cleavage site

Chem Pharm Bull (Tokyo). 1997 Oct;45(10):1631-41. doi: 10.1248/cpb.45.1631.

Authors

Y Yamada¹, K Ando, Y Ikemoto, H Tada, E Shirakawa, E Inagaki, S Shibata, I Nakamura, Y Hayashi, K Ikegami, I Uchida

Affiliation

¹ Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.

PMID: 9353891
DOI: 10.1248/cpb.45.1631

Abstract

A series of renin inhibitors containing the (2S,3S,5S)-2-amino-1-cyclohexyl-6-methyl-3,5-heptanediol (2-amino-3,5-anti-diol) fragment as a novel transition-state mimic was synthesized, and their biological activities were evaluated. All of the synthesized compounds containing the 2-amino-3,5-anti-diol fragment at the P1-P1' position showed high in vitro renin-inhibitory activity with IC50 values in the 10(-8)-10(-10) M range, and most of them caused a reduction of blood pressure when administered orally to salt-depleted, conscious marmosets. The inhibitor (29) with the 4-hydroxypiperidine residue at the P4 position showed the highest activity in terms of both potency and duration of the blood pressure-lowering effect.

Publication types

Comparative Study

MeSH terms

Administration, Oral
Angiotensin-Converting Enzyme Inhibitors / chemical synthesis*
Angiotensin-Converting Enzyme Inhibitors / pharmacology
Animals
Antihypertensive Agents / chemical synthesis*
Antihypertensive Agents / pharmacology
Blood Pressure / drug effects*
Callithrix
Cathepsin D / antagonists & inhibitors
Dipeptides / chemistry*
Fatty Alcohols / chemistry*
Humans
Magnetic Resonance Spectroscopy
Pepsin A / antagonists & inhibitors
Renin / antagonists & inhibitors*
Renin / blood
Renin-Angiotensin System / drug effects
Sodium Chloride
Species Specificity
Spectrometry, Mass, Fast Atom Bombardment
Structure-Activity Relationship

Substances

Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Dipeptides
Fatty Alcohols
N-(1-cyclohexylmethyl-2,4-dihydroxy-5-methylhexyl)-N(alpha)-methyl-N(alpha)-(N-(4-hydroxypiperidino)carbonyl-phenylalanyl)histidinamide
Sodium Chloride
Pepsin A
Renin
Cathepsin D