title: Pyrrolidinyl pyridone and pyrazinone analogues as potent inhibitors of prolyl oligopeptidase (POP).
abstract: We report the synthesis and in vitro activity of a series of novel pyrrolidinyl pyridones and pyrazinones as potent inhibitors of prolyl oligopeptidase (POP). Within this series, compound 39 was co-crystallized within the catalytic site of a human chimeric POP protein which provided a more detailed understanding of how these inhibitors interacted with the key residues within the catalytic pocket.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA. curt.d.haffner@gsk.com
authors.forename: Curt D
authors.initials: CD
authors.lastname: Haffner
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Diaz
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Miller
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reid
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Madauss
authors.forename: Annie
authors.initials: A
authors.lastname: Hassell
authors.forename: Mary H
authors.initials: MH
authors.lastname: Hanlon
authors.forename: David J T
authors.initials: DJ
authors.lastname: Porter
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.forename: Luke H
authors.initials: LH
authors.lastname: Carter
mesh_terms: D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D000085822:Prolyl Oligopeptidases; D011728:Pyridones / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011728:Pyridones; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases