Synthesis and biological evaluation of neutrophilic inflammation inhibitors.
In several non-infectious human diseases, such as ulcerous colitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), the extravasal recruitment of neutrophils plays a crucial role in the development of tissue damage, which, when persistent, can lead to the irreversible organ dysfunction. The neutrophil activation is controlled by a number of intracellular pathways, particularly by a cAMP-dependent protein kinase A (PKA) which also acts on phosphodiesterase IV (PDE4) gene stimulating the synthesis of this enzyme, able to transform cAMP to inactive AMP. PDE4 inhibitors enhance intracellular cAMP and decrease inflammatory cell activation. Several 3-cyclopentyloxy-4-methoxybenzaldehyde and 3-cyclopentyloxy-4-methoxybenzoic acid derivatives were synthesized and studied by us to evaluate their ability to inhibit the superoxide anion production in human neutrophils. These compounds were found able to inhibit the neutrophil activation and some of them increased the cAMP level on tumor necrosis factor-alpha-stimulated neutrophils. Moreover, they also inhibited selectively the human PDE4 enzyme, although they are less potent than the reference compound Rolipram. We report here synthesis, biological studies and some SAR considerations concerning the above mentioned compounds.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV, Genova 3-16132, Italy. obruno@unige.it
Olga
O
Bruno
Chiara
C
Brullo
Nicoletta
N
Arduino
Silvia
S
Schenone
Angelo
A
Ranise
Francesco
F
Bondavalli
Luciano
L
Ottonello
Patrizia
P
Dapino
Franco
F
Dallegri
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D001547:Benzaldehydes; D001565:Benzoates; D001667:Binding, Competitive / Q000187:drug effects; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003517:Cyclopentanes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062425:Hydroxybenzoate Ethers; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D020889:Rolipram / Q000378:metabolism / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
C485662:3-cyclopentyloxy-4-methoxybenzaldehyde; C485663:3-cyclopentyloxy-4-methoxybenzoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001547:Benzaldehydes; D001565:Benzoates; D003517:Cyclopentanes; D062425:Hydroxybenzoate Ethers; D007202:Indicators and Reagents; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D020889:Rolipram