Renin inhibitors containing alpha-heteroatom amino acids as P2 residues.
A series of renin inhibitors having alpha-heteroatom amino acids as P2 substitutions has been prepared. Examples where the heteroatom is oxygen, sulfur, or nitrogen are described. Many of the compounds exhibit subnanomolar potency when tested in vitro against monkey renin. When selected compounds were tested orally in conscious, salt-depleted, normotensive, Cynomolgus monkeys, low to moderate blood pressure lowering was observed. At an oral dose of 30 mg/kg, compound 53a lowered blood pressure by a maximum of 18 mmHg at 2.5 h post-dose.
Repine
J T
JT
Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48106-1047.
Kaltenbronn
J S
JS
Doherty
A M
AM
Hamby
J M
JM
Himmelsbach
R J
RJ
Kornberg
B E
BE
Taylor
M D
MD
Lunney
E A
EA
Humblet
C
C
Rapundalo
S T
ST
D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D002417:Cattle; D006038:Glyoxylates / Q000138:chemical synthesis* / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D000596:Amino Acids; D002402:Cathepsin D; D006038:Glyoxylates; D000092502:Renin Inhibitors