Journal of Enzyme Inhibition and Medicinal Chemistry, Dec 1, 2004
New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive acti... more New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive activity have been discovered. Among the 17 synthesized and tested compounds, five of them showed maximal inhibition of proliferation of concanavallin A (Con A)- stimulated splenocytes at 90 microM, identical to that obtained with cyclosporin A (CsA) at 5 microM, an optimal concentration.
European journal of medicinal chemistry, Aug 1, 2001
This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-... more 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)).
Les thérapies ciblées furent une véritable révolution dans le traitement du CBNPC, cancer le plus... more Les thérapies ciblées furent une véritable révolution dans le traitement du CBNPC, cancer le plus mortel de notre génération. Les laboratoires pharmaceutiques ont mis en place des stratégies aussi novatrices que différentes pour mettre sur le marché ces médicaments innovants. Le testing, véritable lien entre le patient et sa thérapie ciblée, prend une place considérable dans le développement de cette médecine personnalisée.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF
Acta Crystallographica Section C Crystal Structure Communications, 1992
ABSTRACT C14H14N2S, M(r) = 242.3, monoclinic, C2/c, a = 20.004 (2), b = 7.997 (1), c = 15.954 (1)... more ABSTRACT C14H14N2S, M(r) = 242.3, monoclinic, C2/c, a = 20.004 (2), b = 7.997 (1), c = 15.954 (1) angstrom, beta = 90.40 (1)-degrees, V = 2552.2 (7) angstrom 3, Z = 8, D(x) = 1.261 Mg m-3, lambda(Cu K-alphaBAR) = 1.5418 angstrom, mu = 2.0 mm-1, F(000) = 1024, T = 295 (1) K, R = 0.039 for 1807 independent observed reflections. There is a delocalized orbital over the N-C = S thioamide group. The pyridinyl and the phenyl rings are approximately planar and the dihedral angles between their least-squares planes and the NCS thioamide plane are 25.2 (2) and 44.2 (2)-degrees respectively. The molecules form pairs in which they are linked to each other by two weak N(7)-H(7)...N(1i) hydrogen bonds [3.192 (3) angstrom, 177 (3)-degrees] (i: - x, y, 3/2 - z). The title compound shows only a very moderate anti-inflammatory activity, even though it is the thio analog of N-(4,6-dimethylpyridin-2-yl)benzamide which is a non-acidic compound exhibiting a potent anti-inflammatory activity.
The Journal of pharmacology and experimental therapeutics, 1995
We have previously described a family of benzamide derivatives that showed antiinflammatory activ... more We have previously described a family of benzamide derivatives that showed antiinflammatory activity in vivo on carragenin-induced paw edema and experimental cerebral edema. Those compounds inhibited eicosanoids production from activated macrophages (M phi) without inhibiting cyclooxygenase. To further investigate their antiinflammatory activity and compare it to that of classical cyclooxygenase inhibitors, we analyzed their effect on the production of a major proinflammatory cytokine, tumor necrosis factor (TNF-alpha), by in vitro-activated peritoneal macrophages. We show that, in marked contrast with ibuprofen, flurbiprofen and indomethacin which all significantly enhanced TNF production, the two benzamide derivatives tested, JM34 and JM42, significantly inhibited TNF-alpha production by zymosan or lipopolysaccharide-activated M phi. Those compounds did not interfere with the calcium-dependent pathway because they did not affect TNF production of either mice peritoneal M phi or hu...
Journal of Enzyme Inhibition and Medicinal Chemistry, 2005
A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the c... more A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys 119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles ofAsp309 and His480 in the aromatization of the steroid A ring.
The fact that tumour necrosis factor-α (TNF-α) is clearly involved in the pathogenesis of intesti... more The fact that tumour necrosis factor-α (TNF-α) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-α synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-α synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-βpicolyl-tetrafluorophtalimide), on colonic
ABSTRACT A series of 2 polyaza-arylindane-1,3-diones diversely substituted on the heterocycle and... more ABSTRACT A series of 2 polyaza-arylindane-1,3-diones diversely substituted on the heterocycle and the homocycle were synthetized in order to study their anti-inflammatory activity. These enaminodiketones give in alkaline medium polydent anions which can undergo, in presence of electrophilic agents, C, N or O-substitution. The Mitsunobu reaction proved to be the most useful method in attempts to gain regiospecific attack at nitrogen. Pharmacomodulation by the introduction of an ethyl group on the nitrogen of the basic molecule, eventually coupled with 5-methoxylation on the homocycle, proved to be fruitful in the pyridazinyl, pyrimidinyl and tetrazolyl series. Among the 3 most active molecules 31, 43 and 50, the second one was selected for a more detailed pharmacological study.
Bioorganic & Medicinal Chemistry Letters, 2011
A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5... more A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC(50) values ranging from 15 to 60 μM. The reference drug pentamidine presented IC(50)=10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.
Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse ago... more Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse agonists) shows promise to improve metabolic disorders associated with obesity. In this context, we designed and synthetized JM-00266, a new CB1R blocker with limited blood–brain barrier (BBB) permeability. Pharmacokinetics were tested with SwissADME and in vivo in rodents after oral and intraperitoneal administration of JM-00266 in comparison with Rimonabant. In silico predictions indicated JM-00266 is a non-brain penetrant compound and this was confirmed by brain/plasma ratios and brain uptake index values. JM-00266 had no impact on food intake, anxiety-related behavior and body temperature suggesting an absence of central activity. cAMP assays performed in CB1R-transfected HEK293T/17 cells showed that the drug exhibited inverse agonist activity on CB1R. In addition, JM-00266 counteracted anandamide-induced gastroparesis indicating substantial peripheral activity. Acute administration of ...
Journal of Enzyme Inhibition and Medicinal Chemistry, Dec 1, 2004
New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive acti... more New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive activity have been discovered. Among the 17 synthesized and tested compounds, five of them showed maximal inhibition of proliferation of concanavallin A (Con A)- stimulated splenocytes at 90 microM, identical to that obtained with cyclosporin A (CsA) at 5 microM, an optimal concentration.
European journal of medicinal chemistry, Aug 1, 2001
This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-... more 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)).
Les thérapies ciblées furent une véritable révolution dans le traitement du CBNPC, cancer le plus... more Les thérapies ciblées furent une véritable révolution dans le traitement du CBNPC, cancer le plus mortel de notre génération. Les laboratoires pharmaceutiques ont mis en place des stratégies aussi novatrices que différentes pour mettre sur le marché ces médicaments innovants. Le testing, véritable lien entre le patient et sa thérapie ciblée, prend une place considérable dans le développement de cette médecine personnalisée.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF
Acta Crystallographica Section C Crystal Structure Communications, 1992
ABSTRACT C14H14N2S, M(r) = 242.3, monoclinic, C2/c, a = 20.004 (2), b = 7.997 (1), c = 15.954 (1)... more ABSTRACT C14H14N2S, M(r) = 242.3, monoclinic, C2/c, a = 20.004 (2), b = 7.997 (1), c = 15.954 (1) angstrom, beta = 90.40 (1)-degrees, V = 2552.2 (7) angstrom 3, Z = 8, D(x) = 1.261 Mg m-3, lambda(Cu K-alphaBAR) = 1.5418 angstrom, mu = 2.0 mm-1, F(000) = 1024, T = 295 (1) K, R = 0.039 for 1807 independent observed reflections. There is a delocalized orbital over the N-C = S thioamide group. The pyridinyl and the phenyl rings are approximately planar and the dihedral angles between their least-squares planes and the NCS thioamide plane are 25.2 (2) and 44.2 (2)-degrees respectively. The molecules form pairs in which they are linked to each other by two weak N(7)-H(7)...N(1i) hydrogen bonds [3.192 (3) angstrom, 177 (3)-degrees] (i: - x, y, 3/2 - z). The title compound shows only a very moderate anti-inflammatory activity, even though it is the thio analog of N-(4,6-dimethylpyridin-2-yl)benzamide which is a non-acidic compound exhibiting a potent anti-inflammatory activity.
The Journal of pharmacology and experimental therapeutics, 1995
We have previously described a family of benzamide derivatives that showed antiinflammatory activ... more We have previously described a family of benzamide derivatives that showed antiinflammatory activity in vivo on carragenin-induced paw edema and experimental cerebral edema. Those compounds inhibited eicosanoids production from activated macrophages (M phi) without inhibiting cyclooxygenase. To further investigate their antiinflammatory activity and compare it to that of classical cyclooxygenase inhibitors, we analyzed their effect on the production of a major proinflammatory cytokine, tumor necrosis factor (TNF-alpha), by in vitro-activated peritoneal macrophages. We show that, in marked contrast with ibuprofen, flurbiprofen and indomethacin which all significantly enhanced TNF production, the two benzamide derivatives tested, JM34 and JM42, significantly inhibited TNF-alpha production by zymosan or lipopolysaccharide-activated M phi. Those compounds did not interfere with the calcium-dependent pathway because they did not affect TNF production of either mice peritoneal M phi or hu...
Journal of Enzyme Inhibition and Medicinal Chemistry, 2005
A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the c... more A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys 119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles ofAsp309 and His480 in the aromatization of the steroid A ring.
The fact that tumour necrosis factor-α (TNF-α) is clearly involved in the pathogenesis of intesti... more The fact that tumour necrosis factor-α (TNF-α) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-α synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-α synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-βpicolyl-tetrafluorophtalimide), on colonic
ABSTRACT A series of 2 polyaza-arylindane-1,3-diones diversely substituted on the heterocycle and... more ABSTRACT A series of 2 polyaza-arylindane-1,3-diones diversely substituted on the heterocycle and the homocycle were synthetized in order to study their anti-inflammatory activity. These enaminodiketones give in alkaline medium polydent anions which can undergo, in presence of electrophilic agents, C, N or O-substitution. The Mitsunobu reaction proved to be the most useful method in attempts to gain regiospecific attack at nitrogen. Pharmacomodulation by the introduction of an ethyl group on the nitrogen of the basic molecule, eventually coupled with 5-methoxylation on the homocycle, proved to be fruitful in the pyridazinyl, pyrimidinyl and tetrazolyl series. Among the 3 most active molecules 31, 43 and 50, the second one was selected for a more detailed pharmacological study.
Bioorganic & Medicinal Chemistry Letters, 2011
A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5... more A series of 1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (4a-g) and 5-amino-1-aryl-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazoles (5a-g) were synthesized and evaluated in vitro against three Leishmania species: L. amazonensis, L. braziliensis and L. infantum (L. chagasi syn.). The cytotoxicity was assessed. Among the derivatives examined, six compounds emerged as the most active on promastigotes forms of L. amazonensis with IC(50) values ranging from 15 to 60 μM. The reference drug pentamidine presented IC(50)=10 μM. However, these new compounds were less cytotoxic than pentamidine. Based on these results, the more promising derivative 5d was tested further in vivo. This compound showed inhibition of the progression of cutaneous lesions in CBA mice infected with L. amazonensis relative to an untreated control.
Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse ago... more Targeting cannabinoid 1 receptors (CB1R) with peripherally restricted antagonists (or inverse agonists) shows promise to improve metabolic disorders associated with obesity. In this context, we designed and synthetized JM-00266, a new CB1R blocker with limited blood–brain barrier (BBB) permeability. Pharmacokinetics were tested with SwissADME and in vivo in rodents after oral and intraperitoneal administration of JM-00266 in comparison with Rimonabant. In silico predictions indicated JM-00266 is a non-brain penetrant compound and this was confirmed by brain/plasma ratios and brain uptake index values. JM-00266 had no impact on food intake, anxiety-related behavior and body temperature suggesting an absence of central activity. cAMP assays performed in CB1R-transfected HEK293T/17 cells showed that the drug exhibited inverse agonist activity on CB1R. In addition, JM-00266 counteracted anandamide-induced gastroparesis indicating substantial peripheral activity. Acute administration of ...
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