Highly potent, orally active diester macrocyclic human renin inhibitors.
Replacing one amide bond in macrocyclic renin inhibitors of the general structure 1 and 2 with an ester linkage gave glutamate-derived inhibitors 3 and serine-derived inhibitors 4. While this oxygen-for-nitrogen exchange had little effect on potency in the glutamate series, potency was dramatically increased in the serine series. In this series, the 14-membered ring compounds proved to be more potent than the corresponding 13-membered ring derivatives. Substitution of the ring at the position corresponding to P2' generally increased potency. The absolute configuration at this center was shown to be R for the 4-morpholinomethyl derivative (4o), both by asymmetric synthesis and X-ray crystallography. Replacing the "Boc-Phe" moiety of inhibitor 4o with a variety of substituents led to subnanomolar inhibitors, one of which (the "3(S)-quinuclidinyl-Phe" derivative 33) lowered blood pressure 20 mmHg and completely inhibited plasma renin activity for 6 h in sodium-depleted rhesus monkeys. This compound proved to have limited bioavailability (1% in rats) due to cleavage of the serine ester bond and rapid hepatic extraction.
Weber
A E
AE
Department of Exploratory Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065.
Steiner
M G
MG
Krieter
P A
PA
Colletti
A E
AE
Tata
J R
JR
Halgren
T A
TA
Ball
R G
RG
Doyle
J J
JJ
Schorn
T W
TW
Stearns
R A
RA
D000284:Administration, Oral; D000818:Animals; D004952:Esters / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005973:Glutamine / Q000031:analogs & derivatives; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000031:analogs & derivatives; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
D004952:Esters; D005973:Glutamine; D011083:Polycyclic Compounds; D011422:Propionates; D012694:Serine; D000092502:Renin Inhibitors