Cyclic nucleotide phosphodiesterase type 4 inhibitors: evaluation of pyrazolo[1,5-a]-1,3,5-triazine ring system as an adenine bioisostere.
A series of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines were considered as a bioisosteric replacement for the 9-substituted adenine derivatives resulting in the discovery of 8-(2-methoxybenzyl)-4-(N-methylamino)-2-n-propylpyrazolo[1,5-a]-1,3,5-triazine (14d) and 2-trifluoromethyl-8-(2-methoxybenzyl)-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14e) as a new structural class of potent phosphodiesterase type 4 inhibitors (IC(50)=13 nM and 11 nM, respectively) with high isoenzyme selectivity. An original tandem of reactions involving a palladium-mediated cross-coupling reaction (PMCCR) of the readily available 8-iodo-2-methyl-4-(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine (11a) and arylboronic acids or alkynes followed by the displacement of the N-methyl-N-phenylamino group constitute the key steps in a novel synthetic approach developed herein. The treatment of 11a-c with n-BuLi and selected aldehydes represents an interesting alternative to the PMCCR for the synthesis of benzylic derivatives 14a-i. Preliminary biological testing has shown that compounds 14d and 14e strongly inhibit LPS-induced TNFalpha release from human mononuclear cells from healthy subjects. These two compounds were selected for further biological evaluation.
Raboisson
Pierre
P
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7175 du CNRS, Université Louis Pasteur, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch Cedex, France.
Schultz
Dominique
D
Muller
Christian
C
Reimund
Jean-Marie
JM
Pinna
Guillaume
G
Mathieu
Romain
R
Bernard
Philippe
P
Do
Quoc-Tuan
QT
Desjarlais
Renee L
RL
Justiano
Hélène
H
Lugnier
Claire
C
Bourguignon
Jean-Jacques
JJ
D000225:Adenine / Q000737:chemistry*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008744:Methylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D058988:Phosphodiesterase 4 Inhibitors; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C529860:2-trifluoromethyl-8-(2-methoxybenzyl)-4-(N-methylamino)pyrazolo(1,5-a)-1,3,5-triazine; C529859:8-(2-methoxybenzyl)-4-(N-methylamino)-2-n-propylpyrazolo(1,5-a)-1,3,5-triazine; D004791:Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D008070:Lipopolysaccharides; D008744:Methylamines; D058988:Phosphodiesterase 4 Inhibitors; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D010165:Palladium; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000225:Adenine