Substituted 2-[(4-Aminomethyl)phenoxy]-2-methylpropionic Acid PPARα Agonists. 1. Discovery of a Novel Series of Potent HDLc Raising Agents

Sierra, Michael L.; Bénéton, Véronique; Boullay, ‖ Anne-Bénédict; Boyer, Thierry; Brewster, Andrew G.; Donche, Frédéric; Forest, Marie-Claire; Fouchet, Marie-Hélène; Gellibert, Françoise; Grillot, Didier; Lambert, Millard H.; Laroze, Alain; Grumelec, Christelle Le; Linget, Jean Michel; Montana, V.G.; Nguyen, Van-Loc; Nicodème, Edwige; Patel, Vipul P.; Penfornis, Annie; Pineau, Olivier; Pohin, Danig; Potvain, Florent; Poulain, Géraldine; Ruault, Cécile Bertho; Saunders, Michael A.; Toum, Jérôme; Xu, Heng; Xu, and Robert X.; Pianetti, Pascal M.

doi:10.1021/jm058056x

Cited by 114 publications

(100 citation statements)

References 25 publications

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“…The following crystallographic depositions were chosen as baseline for this study; 3VN2 [9] describing the bound co-ordinates of the partial agonist telmisartan to the PPAR _LBP, 2P54 [10] describing the experimental fibrate GW590735 bound to PPAR and 2VST [11] where the endogenous ligand 13-hydroxyoctadecadienoic acid (13-HODE) is bound to PPAR . Another pdb crystallographic deposition, 4ZUD [12] describing the bound co-ordinates of olmesartan to the Ang(II)R was also used in order to assess whether the PPAR and modulators identified in this study through the de novo and Virtual Screening (VS) drug design processes, would also be able to modulate the Ang(II)R and consequently validate the hypothesis of a single entity capable of managing metabolic syndrome.…”

Section: Methodsmentioning

confidence: 99%

“…PDB crystallographic depositions 3VN2 and 2P54 [9,10] describing the bound co-ordinates of telmisartan bound to PPAR and of GW590735 bound to PPAR were used to generate LBP maps and general pharmacophoric structures that described the pharmacophoric space circumscribed by telmisartan and GW590735 when these were docked in their cognate and non-cognate LBPs. The surface volume (Å 3 ) of each generated LBP map was quantified in UCSF Chimera® [19].…”

Section: De Novo Drug Designmentioning

confidence: 99%

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Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Ellul¹,

Shoemake²

2017

Nuclear Receptor Research

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Abstract. This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome-hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR) partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPAR fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPAR and/or _LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the "tried and tested" Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.

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Section: Methodsmentioning

confidence: 99%

Section: De Novo Drug Designmentioning

confidence: 99%

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Ellul¹,

Shoemake²

2017

Nuclear Receptor Research

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“…Reacting 14 with the ammonium trifluoroacetate salt 15a [24] under peptide coupling conditions [30], afforded target compound 10a (Scheme 1). In a similar approach, we prepared an analogue of CC618, 10b, lacking the 5-trifluoromethyl group on the pyridine ring.…”

Section: Synthesis Of the Ligandsmentioning

confidence: 99%

“…The TFAsalts 15a and 15b were prepared by deprotection of the corresponding N-tert butyl carbamates [24] with TFA in MeCN and used without further purification. Compounds 13 [30] and 14 [10] are known compounds. GSK3787 (9) [24] and GW501516 (1) [10] were prepared as previously described.…”

Section: Experimental Section Chemistrymentioning

confidence: 99%

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Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

Kaupang

Paulsen

Steindal

et al. 2015

European Journal of Medicinal Chemistry

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Herein, we describe the synthesis, biological evaluation and molecular docking of the selective PPARβ/δ antagonist (4-methyl-2-(4-(trifluoromethyl)phenyl)-N-(2-(5-(trifluoromethyl)-pyridin-2-ylsulfonyl)ethyl)thiazole-5-carboxamide)), CC618. Results from in vitro luciferase reporter gene assays against the three known human PPAR subtypes revealed that CC618 selectively antagonizes agonist-induced PPARβ/δ activity with an IC50 = 10.0 μM. As observed by LC-MS/MS analysis of tryptic digests, the treatment of PPARβ/δ with CC618 leads to a covalent modification of Cys249, located centrally in the PPARβ/δ ligand binding pocket, corresponding to the conversion of its thiol moiety to a 5-trifluoromethyl-2-pyridylthioether. Finally, molecular docking is employed to shed light on the mode of action of the antagonist and its structural consequences for the PPARβ/δ ligand binding pocket.

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Nuclear Hormone Receptor Medicinal Chemistry

Cheng

Kick

Mukherjee

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter will be focused on recent advances in the medicinal chemistry of agonist, antagonist, and modulator ligands of selected nuclear hormone receptors (NHRs) that are of special interest in the metabolic diseases therapeutic area (diabetes, obesity and dyslipidemia/atherosclerosis). These NHRs include established biological targets such as the peroxisome proliferator‐activated receptors (PPARs), the liver X receptors (LXRs), and the farnesoid X receptors (FXRs), for which ligands have reached either clinical development or have been approved for clinical usage. Other more recent targets of interest to metabolic diseases include HNF and Rev‐erb.

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Substituted 2-[(4-Aminomethyl)phenoxy]-2-methylpropionic Acid PPARα Agonists. 1. Discovery of a Novel Series of Potent HDLc Raising Agents

Cited by 114 publications

References 25 publications

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

Nuclear Hormone Receptor Medicinal Chemistry

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