Design, synthesis and structure-activity relationships of a series of 9-substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors.
Adenine derivatives substituted in position 9 have been demonstrated to have potent cyclic nucleotide phosphodiesterase (PDE) inhibition properties with high selectivity toward PDE-4. Starting from our initial lead compound 9-(2-fluorobenzyl)-N(6)-methyl-2-trifluoromethyladenine (4, NCS613), we designed and synthesized a new series of 9-substituted derivatives for developing structure-activity relationship studies. This new series of derivatives showed increased potencies and better selectivity profiles. Structural modifications were achieved in parallel on three different positions of the adenine ring, and led to the following observations: (i) introduction of a lipophilic substituent such as trifluoromethyl, n-propyl group or iodine in the C-2 position is favourable for both the PDE-4 inhibitory activity and the selectivity towards other isoenzymes; (ii) functionalization of the N9 benzyl group with a 2-methoxy substituent led to remarkably more active compounds; (iii) replacement of the N(6)-methylamino moiety by other amino groups is detrimental to the activity. Among all derivatives prepared, the 9-(2-methoxybenzyl)-N(6)-methyl-2-trifluoromethyladenine (9r), 9-(2-methoxybenzyl)-N(6)-methyl-2-n-propyladenine (9s), and the 2-iodo-9-(2-methoxybenzyl)-N(6)-methyladenine (13b) were found to be the most potent inhibitors within this series (PDE-4-IC(50)=1.4, 7.0, and 0.096 nM, respectively). Compared to our reference compound 4, which showed an IC(50) of 42 nM, the derivative 13b was found 450-fold more potent. Moreover, 2-iodo-9-(2-methoxybenzyl)-N(6)-methyladenine (13b) and 9-(2-methoxybenzyl)-N(6)-methyl-2-trifluoromethyladenine (9r), were at least 50000-150000 times more selective for the PDE-4 than for the other PDE families. Additionally, these new derivatives showed improved efficiency in inhibiting the TNFalpha release from mononuclear cells from healthy subjects (e.g. adenines 7l, 9s and 13b). Thus, compounds 7l, 9r, 9s and 13b are among the most potent and selective PDE-4 inhibitors reported so far and represent very promising pharmacological tools for a better understanding of the signal transduction involving cyclic AMP within the cell: this pathway is implicated in the physiology and the pathophysiology of inflammation, asthma and autoimmune disorders.
Raboisson
Pierre
P
Laboratoire de pharmacochimie de la communication cellulaire, UMR 7081 du CNRS, Université Louis Pasteur, faculté de pharmacie, 74, route du Rhin, BP24, 67401 cedex, Illkirch, France. pierreraboisson@aol.com
Lugnier
Claire
C
Muller
Christian
C
Reimund
Jean-Marie
JM
Schultz
Dominique
D
Pinna
Guillaume
G
Le Bec
Alain
A
Basaran
Hélène
H
Desaubry
Laurent
L
Gaudiot
François
F
Seloum
Mohamed
M
Bourguignon
Jean-Jacques
JJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015195:Drug Design; D006801:Humans; D007118:Immunoassay; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000225:Adenine