title: Highly potent, orally active diester macrocyclic human renin inhibitors.
abstract: 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.
authors.affiliation: Department of Exploratory Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065.
authors.forename: A E
authors.initials: AE
authors.lastname: Weber
authors.forename: M G
authors.initials: MG
authors.lastname: Steiner
authors.forename: P A
authors.initials: PA
authors.lastname: Krieter
authors.forename: A E
authors.initials: AE
authors.lastname: Colletti
authors.forename: J R
authors.initials: JR
authors.lastname: Tata
authors.forename: T A
authors.initials: TA
authors.lastname: Halgren
authors.forename: R G
authors.initials: RG
authors.lastname: Ball
authors.forename: J J
authors.initials: JJ
authors.lastname: Doyle
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
mesh_terms: 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
chemical_list: D004952:Esters; D005973:Glutamine; D011083:Polycyclic Compounds; D011422:Propionates; D012694:Serine; D000092502:Renin Inhibitors