Inhibitors of human renin with C-termini derived from amides and esters of alpha-mercaptoalkanoic acids.
New transition-state analogues bearing C-termini derived from alpha-mercaptoalkanoic acids, esters, and amides were prepared and evaluated as inhibitors of human renin. Addition of alpha-mercaptoalkanoate esters to a chiral Boc-amino epoxide intermediate led ultimately to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. The corresponding sulfoxide and sulfone analogues were also investigated. Some of these derivatives, including one with a stable BocPhe replacement, were relatively potent inhibitors of human plasma renin, having IC50 values below 10 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys (Macaca mulatta) at 0.06-1 mg/kg, they reduced plasma renin activity by 87-94%. However, the accompanying drop in blood pressure was of short duration.
Ashton
W T
WT
Merck Research Laboratories, Rahway, New Jersey 07065.
Cantone
C L
CL
Tolman
R L
RL
Greenlee
W J
WJ
Lynch
R J
RJ
Schorn
T W
TW
Strouse
J F
JF
Siegl
P K
PK
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D012083:Renin / Q000097:blood; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D000092502:Renin Inhibitors
D000577:Amides; D004952:Esters; D012083:Renin; D013438:Sulfhydryl Compounds; D000092502:Renin Inhibitors