title: Discovery of novel non-peptidic ketopiperazine-based renin inhibitors.
abstract: Ketopiperazine 2 was designed from a previously published analog. Compound 2 was shown to be a novel, potent inhibitor of renin that, when administered orally, lowered blood pressure in a hypertensive double transgenic (human renin and angiotensinogen) mouse model. Compound 2 was further optimized to sub-nanomolar potency by designing an analog that addressed the S3 sub-pocket of the renin enzyme (16).
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. daniel.holsworth@pfizer.com <daniel.holsworth@pfizer.com>
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: Noel A
authors.initials: NA
authors.lastname: Powell
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Downing
authors.forename: Cuiman
authors.initials: C
authors.lastname: Cai
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: J Michael
authors.initials: JM
authors.lastname: Ryan
authors.forename: Robert
authors.initials: R
authors.lastname: Ostroski
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: John W
authors.initials: JW
authors.lastname: Bryant
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D000092502:Renin Inhibitors