New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-alpha production inhibitors.
This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNFalpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta-picolyl), allowing significant inhibition of TNFalpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNFalpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 microM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mMkg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID(50) (0.14 microMkg(-1)) comparable with that of N-(2,6-diisopropylphenyl)phthalimide (4) (0.15 microMkg(-1)).
Collin
X
X
Department of Organic Chemistry and Medicinal Chemistry, Faculty of Pharmacy, 1 rue Gaston Veil, F-44035 Cedex, Nantes, France. x.collin@sante.univ-nantes.fr
Robert
J
J
Wielgosz
G
G
Le Baut
G
G
Bobin-Dubigeon
C
C
Grimaud
N
N
Petit
J
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002351:Carrageenan / Q000037:antagonists & inhibitors*; D004427:Ear Diseases / Q000139:chemically induced; D004487:Edema / Q000139:chemically induced; D005534:Foot Diseases / Q000139:chemically induced; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012545:Schiff Bases; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; C445522:N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide; D010797:Phthalimides; D011725:Pyridines; D012545:Schiff Bases; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D013755:Tetradecanoylphorbol Acetate