Novel pyrimidine and 1,3,5-triazine hypolipemic agents

D'Atri, G; Gomarasca, P; Resnati, Giuseppe; Tronconi, G.; Scolastico, Carlo; Sirtori, Cesare R.

doi:10.1021/jm00378a016

Cited by 55 publications

(31 citation statements)

References 1 publication

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“…After subtraction of non transfected control, luciferase activity was normalised for transfection efficacy, divided by DMSO control and by maximum activity to gain relative activation. Calculation of EC values was done using SigmaPlot2001 (SPSS Inc.) The general, synthesis of these compounds has been carried out, adopting a method by d'Atri et al we started with commercially available 2-mercapto-pyrimidine-4,6-diol (2-thiobarbituric acid) [16]. Its sodium salt was alkylated with a-bromo-alkanoic acid ester.…”

Section: Methodsmentioning

confidence: 99%

Quinoline‐Based Derivatives of Pirinixic Acid as Dual PPAR α/γ Agonists

Popescu¹,

Rau²,

Böttcher³

et al. 2007

Archiv der Pharmazie

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Pirinixic acid is known for its peroxisome proliferator-activated receptor (PPAR) agonistic action. In a recent publication, we have shown that aliphatic alpha-substitution of pirinixic acid enhances both PPARalpha and PPARgamma agonism. The goal of this study was to evaluate, whether the PPAR agonism of pirinixic acid may be also maintained in quinoline-based derivatives. The present study revealed that the mere substitution of the dimethyl aniline moiety of pirinixic acid by quinoline leads to a total loss of PPARalpha/gamma agonism, whereas concomitant alpha-substitution with n-butyl or n-hexyl groups restores and even enforces PPAR activation, leading to potent dual PPARalpha/gamma agonists. In the following we report the synthesis of quinoline-based derivatives of pirinixic acid, which in a Gal4-based luciferase-reporter gene assay proved to be potent dual PPARalpha/gamma agonists. Molecular docking of compound 4 with FlexX suggests a binding mode resembling to that of tesaglitazar.

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Section: Methodsmentioning

confidence: 99%

Quinoline‐Based Derivatives of Pirinixic Acid as Dual PPAR α/γ Agonists

Popescu¹,

Rau²,

Böttcher³

et al. 2007

Archiv der Pharmazie

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“…Compounds 4 -11 (Table 1) were synthesized in a four step reaction modified from dAtri et al as shown in Scheme 1 [10]. Reaction of thiobarbituric acid with the appropriate a-bromoalkanoic acid ethylesters (step a) led to the respective thioether derivatives.…”

Section: Chemistrymentioning

confidence: 99%

Novel Pirinixic Acids as PPARα Preferential Dual PPARα/γ Agonists

et al. 2009

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Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that a-alkyl substitution leads to balanced low micromolar-active dual agonists of PPARa and PPARg. Taking a-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPARg activity but further increased PPARa activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPARa ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantioselective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation.

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“…Compounds 5 -17 were generally synthesized based on the method described by d'Atri et al in a four-step reac-tion as shown in Scheme 1 [15]. Reaction of the appropriate bromo ethyl esters 1a -i with thiobarbituric acid (i) led to compounds 2a -i (compounds 1a -h were commercially available, 1i was synthesized by bromination of ethyl-2-naphtylethanoate at its a-position using NBS (Nbromosuccinimide) and dibenzylperoxide in carbon tetrachloride).…”

Section: Synthesismentioning

confidence: 99%

α‐Alkyl Substituted Pirinixic Acid Derivatives as Potent Dual Agonists of the Peroxisome Proliferator Activated Receptor Alpha and Gamma

Rau

Syha

Zettl

et al. 2008

Archiv der Pharmazie

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Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPARalpha subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPARgamma subtype are in clinical use for the treatment of type-2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously activating PPARalpha and PPARgamma seems worthwhile. Starting with pirinixic acid, which is a moderately active dual PPARalpha/gamma agonist, we improved potency at the human PPARalpha and PPARgamma by substituting the alpha-position with an aliphatic chain. The maximal effect was achieved at a chain length of four and six carbons, respectively, leading to an activity induction by a factor of 36 for PPARalpha and 18 for PPARgamma, respectively.

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Novel pyrimidine and 1,3,5-triazine hypolipemic agents

Cited by 55 publications

References 1 publication

Quinoline‐Based Derivatives of Pirinixic Acid as Dual PPAR α/γ Agonists

Quinoline‐Based Derivatives of Pirinixic Acid as Dual PPAR α/γ Agonists

Novel Pirinixic Acids as PPARα Preferential Dual PPARα/γ Agonists

α‐Alkyl Substituted Pirinixic Acid Derivatives as Potent Dual Agonists of the Peroxisome Proliferator Activated Receptor Alpha and Gamma

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