CDP840. A prototype of a novel class of orally active anti-inflammatory phosphodiesterase 4 inhibitors.
The discovery, synthesis and biological activity of a series of triarylethane phosphodiesterase 4 inhibitors is described. Structure-activity relationship studies are presented for CDP840 (29), a potent, chiral, selective inhibitor of PDE 4 (IC(50) 4nM). CDP840 is non-emetic in the ferret at 30mgkg(-1) (po), active in models of inflammation and reverses ozone-induced bronchial hyperreactivity in the guinea pig.
Alexander
R P
RP
Department of Medicinal Chemistry, Celltech R&D Ltd., 208 Bath Road, Slough, Berkshire SL1 3WE, UK. rikki.alexander@celltechgroup.com
Warrellow
G J
GJ
Eaton
M A W
MA
Boyd
E C
EC
Head
J C
JC
Porter
J R
JR
Brown
J A
JA
Reuberson
J T
JT
Hutchinson
B
B
Turner
P
P
Boyce
B
B
Barnes
D
D
Mason
B
B
Cannell
A
A
Taylor
R J
RJ
Zomaya
A
A
Millican
A
A
Leonard
J
J
Morphy
R
R
Wales
M
M
Perry
M
M
Allen
R A
RA
Gozzard
N
N
Hughes
B
B
Higgs
G
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D020889:Rolipram / Q000031:analogs & derivatives; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C102660:CDP 840; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram