title: Synthesis and structure-activity relationships of peptidyl alpha-keto heterocycles as novel inhibitors of prolyl endopeptidase.
abstract: The preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of alpha-keto heterocyclic compounds is described. The design is based on the introduction of alpha-keto heterocycles at the C-terminal end of substrate-like peptides. Many of the compounds including those substituted with thiazole, benzothiazole, benzoxazole, imidazole, and pyridine groups exhibit IC50 potencies of PEP inhibition at nanomolar levels. Structure-activity studies of the C-terminal heterocyclic groups indicate the importance of an sp2 nitrogen atom at a beta-position from the adjoining ketone carbonyl group. This heterocyclic nitrogen atom would provide a critical hydrogen-bond interaction with the histidine residue of the catalytic triad in PEP. Our inhibitors would extend the generality of the alpha-keto heterocycle design to another serine protease.
authors.affiliation: Pharmaceutical Research Laboratory, Meiji Seika Kaisha, Ltd, Yokohama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: T
authors.initials: T
authors.lastname: Okonogi
authors.forename: S
authors.initials: S
authors.lastname: Shibahara
authors.forename: S
authors.initials: S
authors.lastname: Ohuchi
authors.forename: E
authors.initials: E
authors.lastname: Hatsushiba
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
authors.forename: B G
authors.initials: BG
authors.lastname: Christensen
mesh_terms: D000818:Animals; D006860:Hydrogen Bonding; D007668:Kidney / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D000085822:Prolyl Oligopeptidases; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C090023:2-((1-((1-(4-phenylbutanoyl)-2-pyrrolidinyl)carbonyl)-2-pyrrolidinyl)carbonyl)thiazole; C090024:4-((1-((1-(4-phenylbutanoyl)-2-pyrrolidinyl)carbonyl)-2-pyrrolidinyl)carbonyl)thiazole; D011758:Pyrroles; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D012697:Serine Endopeptidases; D000085822:Prolyl Oligopeptidases; D009584:Nitrogen