CDP840: a novel inhibitor of PDE-4.
We present the in vitro characterization of a novel phosphodiesterase type 4 inhibitor, CDP840 (R-[+]-4-[2-¿3-cyclopentyloxy-4-methoxyphenyl¿-2-phenylethyl]pyridine), which has shown efficacy in a phase II allergen challenge study in asthmatics without adverse effects. CDP840 potently inhibits PDE-4 isoenzymes (IC50 2-30 nM) without any effect on PDE-1, 2, 3, 5, and 7 (IC50 > 100 microM). It exhibited no significant selectivity in inhibiting human recombinant isoenzymes PDE-4A, B, C or D and was equally active against the isoenzymes lacking UCR1 (PDE-4B2 and PDE-4D2). In contrast to rolipram, CDP840 acted as a simple competitive inhibitor of all PDE-4 isoenzymes. Studies with rolipram indicated a heterogeneity within all the preparations of PDE-4 isoenzymes, indicative of rolipram inhibiting the catalytic activity of PDE-4 with both a low or high affinity. These observations were confirmed by the use of a PDE-4A variant, PDE-4A330-886, which rolipram inhibited with low affinity (IC50 = 1022 nM). CDP840 in contrast inhibited this PDE-4A variant with similar potency (IC50 = 3.9 nM), which was in good agreement with the Kd of 4.8 nM obtained from [3H]-CDP840 binding studies. Both CDP840 and rolipram inhibited the high-affinity binding of [3H]-rolipram binding to PDE-4A, B, C, and D with similar Kd app (7-19 nM and 3-5 nM, respectively). Thus, the activity of CDP840 at the [3H]-rolipram binding site was in agreement with the inhibitor's activity at the catalytic site. However, rolipram was approximately 100-fold more potent than CDP840 at inhibiting the binding of [3H]-rolipram to mouse brain in vivo. These data clearly demonstrate that CDP840 is a potent selective inhibitor of all PDE-4 isoenzymes. In contrast to rolipram, CDP840 was well-tolerated in humans. This difference, however, cannot at present be attributed to either isoenzyme selectivity or lack of activity in vitro at the high-affinity rolipram binding site (Sr).
Perry
M J
MJ
Celltech Therapeutics Limited, Slough, England. mperry@celltech.co.uk
O'Connell
J
J
Walker
C
C
Crabbe
T
T
Baldock
D
D
Russell
A
A
Lumb
S
S
Huang
Z
Z
Howat
D
D
Allen
R
R
Merriman
M
M
Walls
J
J
Daniel
T
T
Hughes
B
B
Laliberte
F
F
Higgs
G A
GA
Owens
R J
RJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002384:Catalysis / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000037:antagonists & inhibitors / Q000378:metabolism; D020889:Rolipram; D014316:Tritium
D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011760:Pyrrolidinones; D014316:Tritium; C102660:CDP 840; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram