Renin inhibitors containing C-termini derived from mercaptoheterocycles.
A series of transition-state analogues having heterocyclythio C-termini has been synthesized and evaluated for inhibition of human renin. Addition of mercaptoheterocycles to a chiral Boc-amino epoxide intermediate led, after several steps, to the target [(2R,3S)-3-(BocPheHis-amino)-4-cyclohexyl-2-hydroxy-1-butyl]thio derivatives. Oxidation of the thioether to sulfone was also investigated. Several of the compounds, especially those derived from N1-substituted-5-mercaptotetrazoles or N4-substituted-3-mercapto-5-(trifluoromethyl)-1,2,4-triazoles, were moderately potent inhibitors of human plasma renin, having IC50 values of 30-40 nM. When selected compounds were administered intravenously to sodium-deficient rhesus monkeys at 0.3-1.2 mg/kg, they reduced plasma renin activity by 75-98%. However, this inhibition and the accompanying drop in blood pressure were of short duration.
Ashton
W T
WT
Merck Sharp & Dohme Research Laboratories, Rahway, New Jersey 07065.
Cantone
C L
CL
Meurer
L C
LC
Tolman
R L
RL
Greenlee
W J
WJ
Patchett
A A
AA
Lynch
R J
RJ
Schorn
T W
TW
Strouse
J F
JF
Siegl
P K
PK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D012083:Renin / Q000097:blood; D012964:Sodium / Q000172:deficiency; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D000092502:Renin Inhibitors
D012083:Renin; D012964:Sodium; D013438:Sulfhydryl Compounds; D013777:Tetrazoles; D014230:Triazoles; D000092502:Renin Inhibitors