title: Renin inhibitors containing conformationally restricted P1-P1' dipeptide mimetics.
abstract: A series of renin inhibitors containing lactam-bridged P1-P1' dipeptide mimetics based on the ACHPA (4(S)-amino-5-cyclohexyl-3(S)-hydroxypentanoic acid) design was studied. The inhibitors were obtained by aldol addition of various lactams with N alpha-Boc-L-cyclohexylalaninal, followed by Boc group removal and acylation with Boc-Phe-His. The aldol diastereomer having the S configuration at the two newly generated stereogenic centers gave optimal enzyme inhibition. Potency was further enhanced in the gamma-lactam ring series by substitution with small hydrophobic groups to mimic the P1' side chain of the renin substrate. Thus, 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl-1 - (1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)propane (34) has an IC50 of 1.3 nM in the human plasma renin assay. A variety of substituents on the lactam nitrogen are tolerated and can be used to vary the physical properties of the inhibitor. By using a model of the human renin active site, the conformation of 34 in the enzyme-inhibitor complex is proposed. This modeled conformation is very similar to the solid-state conformation of 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl- 1-(1-methyl-2-oxopyrrolidin-3(S)-yl)propane (36), the structure of which was determined by single-crystal X-ray diffraction analysis. The most potent ACH-PA-lactam renin inhibitors show good selectivity when assayed against other types of aspartic proteinases. By varying the lactam ring substituents, potent and selective inhibitors of cathepsin D and cathepsin E can be obtained.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: P D
authors.initials: PD
authors.lastname: Williams
authors.forename: D S
authors.initials: DS
authors.lastname: Perlow
authors.forename: L S
authors.initials: LS
authors.lastname: Payne
authors.forename: M K
authors.initials: MK
authors.lastname: Holloway
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: R J
authors.initials: RJ
authors.lastname: Lynch
authors.forename: J J
authors.initials: JJ
authors.lastname: Doyle
authors.forename: J F
authors.initials: JF
authors.lastname: Strouse
authors.forename: G P
authors.initials: GP
authors.lastname: Vlasuk
mesh_terms: D000818:Animals; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D004151:Dipeptides; D005260:Female; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
chemical_list: D004151:Dipeptides; D009842:Oligopeptides; D012083:Renin; D000092502:Renin Inhibitors; C051529:renin inhibitory peptide, 4-amino-5-cyclohexyl-3-hydroxypentanoic acid