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.
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.
Yamada
Y
Y
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
Ando
K
K
Ikemoto
Y
Y
Tada
H
H
Shirakawa
E
E
Inagaki
E
E
Shibata
S
S
Nakamura
I
I
Hayashi
Y
Y
Ikegami
K
K
Uchida
I
I
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D002144:Callithrix; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D004151:Dipeptides / Q000737:chemistry*; D005233:Fatty Alcohols / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010434:Pepsin A / Q000037:antagonists & inhibitors; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D012965:Sodium Chloride; D013045:Species Specificity; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002402:Cathepsin D; D004151:Dipeptides; D005233:Fatty Alcohols; D010434:Pepsin A; D012083:Renin; D012965:Sodium Chloride; D000092502:Renin Inhibitors; C109430:N-(1-cyclohexylmethyl-2,4-dihydroxy-5-methylhexyl)-N(alpha)-methyl-N(alpha)-(N-(4-hydroxypiperidino)carbonyl-phenylalanyl)histidinamide