Thiophene inhibitors of PDE4: crystal structures show a second binding mode at the catalytic domain of PDE4D2.
PDE4 inhibitors have been identified as therapeutic targets for a variety of conditions, particularly inflammatory diseases. We have serendipitously identified a novel class of phosphodiesterase 4 (PDE4) inhibitor during a study to discover antagonists of the parathyroid hormone receptor. X-ray crystallographic studies of PDE4D2 complexed to four potent inhibitors reveal the atomic details of how they inhibit the enzyme and a notable contrast to another recently reported thiophene-based inhibitor.
Medicinal Chemistry & Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria, Australia.
Jacob L
JL
Nankervis
Susanne C
SC
Feil
Nancy C
NC
Hancock
Zhaohua
Z
Zheng
Hooi-Ling
HL
Ng
Craig J
CJ
Morton
Jessica K
JK
Holien
Patricia W M
PW
Ho
Mark M
MM
Frazzetto
Ian G
IG
Jennings
David T
DT
Manallack
T John
TJ
Martin
Philip E
PE
Thompson
Michael W
MW
Parker
D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry*; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D058988:Phosphodiesterase 4 Inhibitors; D013876:Thiophenes; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4