Pyrrolidinyl pyridone and pyrazinone analogues as potent inhibitors of prolyl oligopeptidase (POP).
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.
Haffner
Curt D
CD
Department of Medicinal Chemistry, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA. curt.d.haffner@gsk.com
Diaz
Caroline J
CJ
Miller
Aaron B
AB
Reid
Robert A
RA
Madauss
Kevin P
KP
Hassell
Annie
A
Hanlon
Mary H
MH
Porter
David J T
DJ
Becherer
J David
JD
Carter
Luke H
LH
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*
D011728:Pyridones; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases