title: Benzyl ether structure-activity relationships in a series of ketopiperazine-based renin inhibitors.
abstract: Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(pi+sigma) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.
authors.affiliation: Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. noel.powell@pfizer.com
authors.forename: Noel A
authors.initials: NA
authors.lastname: Powell
authors.forename: Emma H
authors.initials: EH
authors.lastname: Clay
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Holsworth
authors.forename: John W
authors.initials: JW
authors.lastname: Bryant
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004986:Ether; D006801:Humans; D020128:Inhibitory Concentration 50; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004986:Ether; D000077489:Piperazine; D010879:Piperazines; D000092502:Renin Inhibitors; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human