Philippe Pflieger - Academia.edu (original) (raw)
Papers by Philippe Pflieger
PubMed, Apr 1, 1996
The primary metabolites of a series of unsaturated lauric acid analogs (8-, 9-, 10-, and 11-dodec... more The primary metabolites of a series of unsaturated lauric acid analogs (8-, 9-, 10-, and 11-dodecenoic acids) used as radiolabeled substrates for rat liver microsomes were quantitated by TLC and reverse phase-HPLC analysis, and identified by chemical derivation and GC/MS. Isomeric epoxidodecanoic acids and omega- and (omega-1)-monohydroxydodecenoic acids were essentially the only products formed from the incubations of the unsaturated fatty acids. Rat liver microsomes predominantly oxidized the terminal carbons of all substrates, leading to omega- and (omega-1)-hydroxylated metabolites, with the exception of 11-dodecenoic acid, which was efficiently converted to the epoxide. The E and Z isomers of dodecenoic acids were metabolized with the same efficiency and gave rise to the same pattern of hydroxylated vs. epoxidized products. The hydroxylation/epoxidation ratio was directly related to the position, but not to the geometry of the double bond in the aliphatic chain. Clofibrate pretreatment of the animals resulted in a strong induction of omega-oxidation, with a decrease in the ability to catalyze epoxidation of internal olefins, whereas phenobarbital pretreatment only stimulated (omega-1)-hydroxylation without any effect on epoxidation. In contrast to higher plants in which carbon 9 is the major target, rat liver cytochromes P450 selectively carried out hydroxylation (or epoxidation) at carbons 12 and 11 of lauric acid, as well as its unsaturated isomeric analogs.
La metabolisation d'acides gras par des monooxygenases a cytochrome p-450 des plantes superie... more La metabolisation d'acides gras par des monooxygenases a cytochrome p-450 des plantes superieures est examinee dans le but de comprendre la reactivite et la specificite de ces enzymes. Purete optique et configuration absolue des produits d'hydroxylation sont determines
![Research paper thumbnail of A pyrimido[1,6-a]benzimidazole that enhances DNA cleavage mediated by eukaryotic topoisomerase II: a novel class of topoisomerase II-targeted drugs with cytotoxic potential](https://attachments.academia-assets.com/96014387/thumbnails/1.jpg)
](Antimicrobial Agents and Chemotherapy, 1993
Recently, a number of novel quinolones with potent activity against topoisomerase II and eukaryot... more Recently, a number of novel quinolones with potent activity against topoisomerase II and eukaryotic cells have been described. Many of these compounds contain aromatic substituents in their C-7 ring positions. To determine whether pyrimido[1,6-a]benzimidazoles, a class of drugs modeled on quinolones, also display activity toward eukaryotic systems, the effects of Ro 46-7864 and Ro 47-3359 on Drosophila melanogaster topoisomerase II and Kc cells were characterized. While the former drug contains an aliphatic group (4-N-methylpiperazine) at the ring position equivalent to C-7 in quinolones, the latter compound contains an aromatic substituent (2,6-dimethylpyridine). Both pyrimido[1,6-a]benzimidazoles inhibited DNA relaxation catalyzed by the type II enzyme. However, only Ro 47-3359 enhanced topoisomerase II-mediated DNA cleavage and was toxic to Kc cells. At a concentration of 100 microM, this drug approximately doubled the levels of DNA breakage in vitro and killed > 50% of the in...
A compound of formula ** ** Formula wherein R1 is phenyl, optionally substituted with halogen, C1... more A compound of formula ** ** Formula wherein R1 is phenyl, optionally substituted with halogen, C1-7 alkyl, C3-6 cycloalkyl, C1-7 alkoxy, cyano, C1-7 alkyl substituted with halogen, C1-7 alkyl substituted with hydroxy, C1-7 alkoxy substituted with halogen or C1-7 alkoxy substituted with hydroxy; or is pyridin-2, 3 or 4-yl, optionally substituted by halogen, C1-7 alkyl, C3-6 cycloalkyl, cyano, C1-7 alkyl substituted with halogen, C1-7 alkyl substituted with hydroxy, C1-7 alkoxy, C1-7 alkoxy substituted with halogen, or C1-7 alkoxy substituted with hydroxy; or is pyrimidin-2, 4 or 5-yl, optionally substituted by halogen, C1-7 alkyl, C3-6-cycloalkyl, C1-7 alkyl substituted with hydroxy or C1-7 alkyl substituted with halogen, or pyrazin-2- yl, optionally substituted by halogen, C1-7 alkyl, C3-6 cycloalkyl, C1-7 alkyl substituted with halogen, C1-7 alkyl substituted with hydroxy or cyano, or is 2,2-difluorobenzo [d] [1,3] dioxol-5-yl or thiazolyl, optionally substituted with C1-7 alkyl su...
Selon l'invention, les composes de la formule, dans laquelle R?1, R2, R3, R4, A1 et A2? ont l... more Selon l'invention, les composes de la formule, dans laquelle R?1, R2, R3, R4, A1 et A2? ont la signification donnee dans la revendication 1, ainsi que des sels, solvates et esters utilisables dans le domaine pharmaceutique, peuvent etre utilises sous forme de preparations pharmaceutiques destinees au traitement ou a la prevention de l'arthrite, des maladies cardio-vasculaires, du diabete, de l'insuffisance renale, des troubles alimentaires et de l'obesite.
Journal of Hypertension, 2010
Objective The increased mortality observed with the cholesteryl ester transfer protein inhibitor ... more Objective The increased mortality observed with the cholesteryl ester transfer protein inhibitor torcetrapib is partly due to increased aldosterone production and blood pressure. The mechanisms underlying these effects were investigated. Methods Cytochrome P450 subunit 11B2 (aldosterone synthase), extracellular signal-regulated kinase (p44/42) and voltage-gated Ca 2þ channel alpha subunit mRNA profiling, aldosterone production, cytosolic calcium and RNA interference were assessed in adrenocarcinoma human cells (H295R). Telemetry was conducted in spontaneously hypertensive rats. Results Torcetrapib and angiotensin II (Ang II) but not dalcetrapib (a structurally different cholesteryl ester transfer protein inhibitor) elevated both cytochrome P450 subunit 11B2 mRNA and aldosterone production in H295R cells at 6 h. At days 1-5, torcetrapib produced a sustained increase of cytochrome P450 subunit 11B2 mRNA, unlike Ang II. Although torcetrapib and Ang II potentiated the effect of 25-OH cholesterol and raised pregnenolone levels, torcetrapib increased neither cytosolic Ca 2þ at 5 min nor extracellular signal-regulated kinase1/2 phosphorylation, suggesting initially divergent pathways. Unlike Ang II, torcetrapib steroidogenesis was not affected by Ang II type 1 receptor antagonism or voltage-gated T-type Ca 2þ channel antagonism, but was blocked by several L-type Ca 2þ channel antagonists. In unbiased genome-wide screening, Ang II and torcetrapib modulated an overlapping but distinct set of genes in H295R cells. Torcetrapib, but not Ang II, upregulated mRNA levels of the L-type Ca 2þ channel alpha 1C subunit. In spontaneously hypertensive rat, torcetrapib had a potent hypertensive effect mediated by the L-type Ca 2þ channel. Conclusion The unique steroidogenic and hypertensive side effects of torcetrapib may be linked and involve voltage-gated L-type Ca 2þ channels. Structurally unrelated cholesteryl ester transfer protein inhibitors such as dalcetrapib do not share this effect.
A compound of formula I ** Formula ** in queR1, R2, R4 and R5 are independently hydrogen, C1-C6al... more A compound of formula I ** Formula ** in queR1, R2, R4 and R5 are independently hydrogen, C1-C6alkyl, C1-C6alkoxy or halogen; R3 is C1-C6 alkyl, halogeno-C1-C6 , C3-C6 cycloalkyl, Si (C1-C6alkyl) 3, -OR12, wherein R12 is C1-C6alkyl, halogeno-C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, benzyl or S (O) 2-alkyl C1-C6, or pentafluorsulfuranilo; or R2 and R3 together with the carbon atoms to which they are attached form a carbocyclic 5- or 6-membered oun heterocyclic 5- or 6-membered ring containing one or two heteroatoms selected from N, O and S; R6 is hydrogen or C1-C6 alkyl; R7 and R8 are independently hydrogen, C1-C6 alkyl, hydroxy or halogen; R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halogeno-C1-C6 alkyl, heterocyclyl , heteroaryl, phenyl, naphthyl, -OR13, wherein R13 is C1-C6 or phenyl, -NR14R15 alkyl wherein R14 and R15 are independently hydrogen, C1-C6 alkyl or phenyl, or -C (O) - OR16, wherein R16 is hydrogen or C1-C6 alkyl; R10 and R11 are independently hydrogen, halogen, C1-C6 al...
L'invention concerne des 5-benzyl-2,4-diaminopyrimidines substituees de la formule generale (... more L'invention concerne des 5-benzyl-2,4-diaminopyrimidines substituees de la formule generale (A) ou R1 represente alkyle C2-C3 et R2 represente heterocyclyle, phenyle ou naphtyle, lie par un de ses atomes de carbone ; R3 represente alkyle C2-C6, alkenyle, cycloalkyle, cycloalkylalkyle, heterocyclyalkyle, alkylsulfonyle, cycloalkylsulfonyle, cycloalkylalkylsulfamoyle, heterocyclylsulfonyle, heterocyclyalkylsulfonyle ou dialkylsulfamoyle; sachant que alkyle, cycloalkyle et alkenyle seuls ou en compositions peuvent porter jusqu'a 6 atomes de carbone, heterocyclyle seul ou en compositions peut porter jusqu'a 6 termes cycliques et les groupes R2 et R3 peuvent etre substitues, ainsi que des sels d'addition d'acide de ces composes. L'invention concerne egalement un procede de production des 5-benzyl-2,4-diaminopyrimidines susmentionnees, les produits intermediaires en resultant, les medicaments correspondants et l'utilisation des 5-benzyl-2,4-diaminopyrimidines c...
L'invention concerne des composes de formule (I), des procedes pour les preparer, leur utilis... more L'invention concerne des composes de formule (I), des procedes pour les preparer, leur utilisation en tant que produits pharmaceutiques et des compositions pharmaceutiques les comprenant.
PubMed, Apr 1, 1996
The primary metabolites of a series of unsaturated lauric acid analogs (8-, 9-, 10-, and 11-dodec... more The primary metabolites of a series of unsaturated lauric acid analogs (8-, 9-, 10-, and 11-dodecenoic acids) used as radiolabeled substrates for rat liver microsomes were quantitated by TLC and reverse phase-HPLC analysis, and identified by chemical derivation and GC/MS. Isomeric epoxidodecanoic acids and omega- and (omega-1)-monohydroxydodecenoic acids were essentially the only products formed from the incubations of the unsaturated fatty acids. Rat liver microsomes predominantly oxidized the terminal carbons of all substrates, leading to omega- and (omega-1)-hydroxylated metabolites, with the exception of 11-dodecenoic acid, which was efficiently converted to the epoxide. The E and Z isomers of dodecenoic acids were metabolized with the same efficiency and gave rise to the same pattern of hydroxylated vs. epoxidized products. The hydroxylation/epoxidation ratio was directly related to the position, but not to the geometry of the double bond in the aliphatic chain. Clofibrate pretreatment of the animals resulted in a strong induction of omega-oxidation, with a decrease in the ability to catalyze epoxidation of internal olefins, whereas phenobarbital pretreatment only stimulated (omega-1)-hydroxylation without any effect on epoxidation. In contrast to higher plants in which carbon 9 is the major target, rat liver cytochromes P450 selectively carried out hydroxylation (or epoxidation) at carbons 12 and 11 of lauric acid, as well as its unsaturated isomeric analogs.
La metabolisation d'acides gras par des monooxygenases a cytochrome p-450 des plantes superie... more La metabolisation d'acides gras par des monooxygenases a cytochrome p-450 des plantes superieures est examinee dans le but de comprendre la reactivite et la specificite de ces enzymes. Purete optique et configuration absolue des produits d'hydroxylation sont determines
Antimicrobial Agents and Chemotherapy, 1993
Recently, a number of novel quinolones with potent activity against topoisomerase II and eukaryot... more Recently, a number of novel quinolones with potent activity against topoisomerase II and eukaryotic cells have been described. Many of these compounds contain aromatic substituents in their C-7 ring positions. To determine whether pyrimido[1,6-a]benzimidazoles, a class of drugs modeled on quinolones, also display activity toward eukaryotic systems, the effects of Ro 46-7864 and Ro 47-3359 on Drosophila melanogaster topoisomerase II and Kc cells were characterized. While the former drug contains an aliphatic group (4-N-methylpiperazine) at the ring position equivalent to C-7 in quinolones, the latter compound contains an aromatic substituent (2,6-dimethylpyridine). Both pyrimido[1,6-a]benzimidazoles inhibited DNA relaxation catalyzed by the type II enzyme. However, only Ro 47-3359 enhanced topoisomerase II-mediated DNA cleavage and was toxic to Kc cells. At a concentration of 100 microM, this drug approximately doubled the levels of DNA breakage in vitro and killed > 50% of the in...
A compound of formula ** ** Formula wherein R1 is phenyl, optionally substituted with halogen, C1... more A compound of formula ** ** Formula wherein R1 is phenyl, optionally substituted with halogen, C1-7 alkyl, C3-6 cycloalkyl, C1-7 alkoxy, cyano, C1-7 alkyl substituted with halogen, C1-7 alkyl substituted with hydroxy, C1-7 alkoxy substituted with halogen or C1-7 alkoxy substituted with hydroxy; or is pyridin-2, 3 or 4-yl, optionally substituted by halogen, C1-7 alkyl, C3-6 cycloalkyl, cyano, C1-7 alkyl substituted with halogen, C1-7 alkyl substituted with hydroxy, C1-7 alkoxy, C1-7 alkoxy substituted with halogen, or C1-7 alkoxy substituted with hydroxy; or is pyrimidin-2, 4 or 5-yl, optionally substituted by halogen, C1-7 alkyl, C3-6-cycloalkyl, C1-7 alkyl substituted with hydroxy or C1-7 alkyl substituted with halogen, or pyrazin-2- yl, optionally substituted by halogen, C1-7 alkyl, C3-6 cycloalkyl, C1-7 alkyl substituted with halogen, C1-7 alkyl substituted with hydroxy or cyano, or is 2,2-difluorobenzo [d] [1,3] dioxol-5-yl or thiazolyl, optionally substituted with C1-7 alkyl su...
Selon l'invention, les composes de la formule, dans laquelle R?1, R2, R3, R4, A1 et A2? ont l... more Selon l'invention, les composes de la formule, dans laquelle R?1, R2, R3, R4, A1 et A2? ont la signification donnee dans la revendication 1, ainsi que des sels, solvates et esters utilisables dans le domaine pharmaceutique, peuvent etre utilises sous forme de preparations pharmaceutiques destinees au traitement ou a la prevention de l'arthrite, des maladies cardio-vasculaires, du diabete, de l'insuffisance renale, des troubles alimentaires et de l'obesite.
Journal of Hypertension, 2010
Objective The increased mortality observed with the cholesteryl ester transfer protein inhibitor ... more Objective The increased mortality observed with the cholesteryl ester transfer protein inhibitor torcetrapib is partly due to increased aldosterone production and blood pressure. The mechanisms underlying these effects were investigated. Methods Cytochrome P450 subunit 11B2 (aldosterone synthase), extracellular signal-regulated kinase (p44/42) and voltage-gated Ca 2þ channel alpha subunit mRNA profiling, aldosterone production, cytosolic calcium and RNA interference were assessed in adrenocarcinoma human cells (H295R). Telemetry was conducted in spontaneously hypertensive rats. Results Torcetrapib and angiotensin II (Ang II) but not dalcetrapib (a structurally different cholesteryl ester transfer protein inhibitor) elevated both cytochrome P450 subunit 11B2 mRNA and aldosterone production in H295R cells at 6 h. At days 1-5, torcetrapib produced a sustained increase of cytochrome P450 subunit 11B2 mRNA, unlike Ang II. Although torcetrapib and Ang II potentiated the effect of 25-OH cholesterol and raised pregnenolone levels, torcetrapib increased neither cytosolic Ca 2þ at 5 min nor extracellular signal-regulated kinase1/2 phosphorylation, suggesting initially divergent pathways. Unlike Ang II, torcetrapib steroidogenesis was not affected by Ang II type 1 receptor antagonism or voltage-gated T-type Ca 2þ channel antagonism, but was blocked by several L-type Ca 2þ channel antagonists. In unbiased genome-wide screening, Ang II and torcetrapib modulated an overlapping but distinct set of genes in H295R cells. Torcetrapib, but not Ang II, upregulated mRNA levels of the L-type Ca 2þ channel alpha 1C subunit. In spontaneously hypertensive rat, torcetrapib had a potent hypertensive effect mediated by the L-type Ca 2þ channel. Conclusion The unique steroidogenic and hypertensive side effects of torcetrapib may be linked and involve voltage-gated L-type Ca 2þ channels. Structurally unrelated cholesteryl ester transfer protein inhibitors such as dalcetrapib do not share this effect.
A compound of formula I ** Formula ** in queR1, R2, R4 and R5 are independently hydrogen, C1-C6al... more A compound of formula I ** Formula ** in queR1, R2, R4 and R5 are independently hydrogen, C1-C6alkyl, C1-C6alkoxy or halogen; R3 is C1-C6 alkyl, halogeno-C1-C6 , C3-C6 cycloalkyl, Si (C1-C6alkyl) 3, -OR12, wherein R12 is C1-C6alkyl, halogeno-C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, benzyl or S (O) 2-alkyl C1-C6, or pentafluorsulfuranilo; or R2 and R3 together with the carbon atoms to which they are attached form a carbocyclic 5- or 6-membered oun heterocyclic 5- or 6-membered ring containing one or two heteroatoms selected from N, O and S; R6 is hydrogen or C1-C6 alkyl; R7 and R8 are independently hydrogen, C1-C6 alkyl, hydroxy or halogen; R9 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halogeno-C1-C6 alkyl, heterocyclyl , heteroaryl, phenyl, naphthyl, -OR13, wherein R13 is C1-C6 or phenyl, -NR14R15 alkyl wherein R14 and R15 are independently hydrogen, C1-C6 alkyl or phenyl, or -C (O) - OR16, wherein R16 is hydrogen or C1-C6 alkyl; R10 and R11 are independently hydrogen, halogen, C1-C6 al...
L'invention concerne des 5-benzyl-2,4-diaminopyrimidines substituees de la formule generale (... more L'invention concerne des 5-benzyl-2,4-diaminopyrimidines substituees de la formule generale (A) ou R1 represente alkyle C2-C3 et R2 represente heterocyclyle, phenyle ou naphtyle, lie par un de ses atomes de carbone ; R3 represente alkyle C2-C6, alkenyle, cycloalkyle, cycloalkylalkyle, heterocyclyalkyle, alkylsulfonyle, cycloalkylsulfonyle, cycloalkylalkylsulfamoyle, heterocyclylsulfonyle, heterocyclyalkylsulfonyle ou dialkylsulfamoyle; sachant que alkyle, cycloalkyle et alkenyle seuls ou en compositions peuvent porter jusqu'a 6 atomes de carbone, heterocyclyle seul ou en compositions peut porter jusqu'a 6 termes cycliques et les groupes R2 et R3 peuvent etre substitues, ainsi que des sels d'addition d'acide de ces composes. L'invention concerne egalement un procede de production des 5-benzyl-2,4-diaminopyrimidines susmentionnees, les produits intermediaires en resultant, les medicaments correspondants et l'utilisation des 5-benzyl-2,4-diaminopyrimidines c...
L'invention concerne des composes de formule (I), des procedes pour les preparer, leur utilis... more L'invention concerne des composes de formule (I), des procedes pour les preparer, leur utilisation en tant que produits pharmaceutiques et des compositions pharmaceutiques les comprenant.