title: Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors.
abstract: Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P2-P1'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC50 0.61, 0.59, 0.65 microM, respectively). Modification of inhibitor 3 at P4 led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: A E
authors.initials: AE
authors.lastname: Weber
authors.forename: T A
authors.initials: TA
authors.lastname: Halgren
authors.forename: J J
authors.initials: JJ
authors.lastname: Doyle
authors.forename: R J
authors.initials: RJ
authors.lastname: Lynch
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
authors.forename: W H
authors.initials: WH
authors.lastname: Parsons
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000092502:Renin Inhibitors