|
Maximum transcriptional activation of human PPAR delta receptor
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.
Year : 2003
Volume : 13
Issue : 9
First Page : 1517
Last Page : 1521
Authors : Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR, Sternbach DD.
Abstract : We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
|
Binding affinity for human PPAR delta receptor
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.
Year : 2003
Volume : 13
Issue : 9
First Page : 1517
Last Page : 1521
Authors : Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR, Sternbach DD.
Abstract : We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
|
Activity against murine PPAR delta receptor
|
Mus musculus
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.
Year : 2003
Volume : 13
Issue : 9
First Page : 1517
Last Page : 1521
Authors : Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR, Sternbach DD.
Abstract : We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
|
Maximum transcriptional activation of human PPAR gamma receptor
|
Homo sapiens
|
850.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity.
Year : 2003
Volume : 13
Issue : 9
First Page : 1517
Last Page : 1521
Authors : Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR, Sternbach DD.
Abstract : We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor delta (PPARdelta). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC(50) of 1.1 nM against PPARdelta with 1000-fold selectivity over the other human subtypes.
|
Agonist activity at PPARdelta by transactivation assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,4,5-Trisubstituted isoxazoles as novel PPARdelta agonists: Part 1.
Year : 2006
Volume : 16
Issue : 16
First Page : 4376
Last Page : 4380
Authors : Epple R, Russo R, Azimioara M, Cow C, Xie Y, Wang X, Wityak J, Karanewsky D, Gerken A, Iskandar M, Saez E, Martin Seidel H, Tian SS.
Abstract : We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARdelta. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif.
|
Activity at PPARbeta/delta by luciferase reporter gene transactivation assay in COS7 cells
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Studies towards the conception of new selective PPARbeta/delta ligands.
Year : 2006
Volume : 16
Issue : 17
First Page : 4528
Last Page : 4532
Authors : Basséne CE, Suzenet F, Hennuyer N, Staels B, Caignard DH, Dacquet C, Renard P, Guillaumet G.
Abstract : In order to define new PPARbeta/delta ligands, SAR study on the selective PPARbeta/delta activator L-165,041 led to the identification of one key functional group for selective PPARbeta/delta activation. Furthermore, taking advantage of SAR studies done elsewhere on the most selective PPARbeta/delta ligand GW501516, the conception of new ligands showing good affinity for PPARbeta/delta is reported. Finally, synthesis and biological evaluation of pyridine analogues have shown the benefical effect of the pyridine ring on the PPARbeta/delta subtype selectivity.
|
Agonist potency at PPARdelta in CV1 cells by cell based transient transfection assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.
Year : 2007
Volume : 50
Issue : 4
First Page : 685
Last Page : 695
Authors : Sierra ML, Beneton V, Boullay AB, Boyer T, Brewster AG, Donche F, Forest MC, Fouchet MH, Gellibert FJ, Grillot DA, Lambert MH, Laroze A, Le Grumelec C, Linget JM, Montana VG, Nguyen VL, Nicodème E, Patel V, Penfornis A, Pineau O, Pohin D, Potvain F, Poulain G, Ruault CB, Saunders M, Toum J, Xu HE, Xu RX, Pianetti PM.
Abstract : The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.
|
Activity at human placenta PPAR delta expressed in HEK293 cells by PPAR-GAL4 transactivation assay
|
Homo sapiens
|
7.9
nM
|
|
Journal : J. Med. Chem.
Title : Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.
Year : 2007
Volume : 50
Issue : 7
First Page : 1495
Last Page : 1503
Authors : Sauerberg P, Olsen GS, Jeppesen L, Mogensen JP, Pettersson I, Jeppesen CB, Daugaard JR, Galsgaard ED, Ynddal L, Fleckner J, Panajotova V, Polivka Z, Pihera P, Havranek M, Wulff EM.
Abstract : The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.
|
Effect on fatty acid oxidation in rat L6 cells
|
Rattus norvegicus
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.
Year : 2007
Volume : 50
Issue : 7
First Page : 1495
Last Page : 1503
Authors : Sauerberg P, Olsen GS, Jeppesen L, Mogensen JP, Pettersson I, Jeppesen CB, Daugaard JR, Galsgaard ED, Ynddal L, Fleckner J, Panajotova V, Polivka Z, Pihera P, Havranek M, Wulff EM.
Abstract : The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.
|
Agonist activity at mouse PPAR delta expressed in HEK293 cells by PPAR-GAL4 transactivation assay
|
Mus musculus
|
54.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and synthesis of a novel selective partial PPARdelta agonist with full efficacy on lipid metabolism in vitro and in vivo.
Year : 2007
Volume : 50
Issue : 7
First Page : 1495
Last Page : 1503
Authors : Sauerberg P, Olsen GS, Jeppesen L, Mogensen JP, Pettersson I, Jeppesen CB, Daugaard JR, Galsgaard ED, Ynddal L, Fleckner J, Panajotova V, Polivka Z, Pihera P, Havranek M, Wulff EM.
Abstract : The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.
|
Effect on PPARdelta transactivation activity in HEK293 cells
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists.
Year : 2007
Volume : 15
Issue : 15
First Page : 5177
Last Page : 5190
Authors : Kasuga J, Nakagome I, Aoyama A, Sako K, Ishizawa M, Ogura M, Makishima M, Hirono S, Hashimoto Y, Miyachi H.
Abstract : A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARdelta transactivation activity, comparable with or somewhat superior to that of the known PPARdelta-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARdelta function, but also as a candidate drug for the treatment of metabolic syndrome.
|
Displacement of [3H]2-(4-(3-(4-acetyl-3-hydroxy-2 propyl-phenoxy)propoxy)phenoxy)acetic acid from human PPARdelta after 30 mins by SPA
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of selective benzothiophene, benzofuran, and indole-based peroxisome proliferator-activated receptor delta agonists.
Year : 2007
Volume : 17
Issue : 13
First Page : 3630
Last Page : 3635
Authors : Filzen GF, Bratton L, Cheng XM, Erasga N, Geyer A, Lee C, Lu G, Pulaski J, Sorenson RJ, Unangst PC, Trivedi BK, Xu X.
Abstract : Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
|
Displacement of [3H]2-(4-(2-(3-(2,4-difluorophenyl)-1-heptylureido)ethyl)phenoxy)-2-methylbutanoic acid from human PPARalpha after 30 mins by SPA
|
Homo sapiens
|
463.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of selective benzothiophene, benzofuran, and indole-based peroxisome proliferator-activated receptor delta agonists.
Year : 2007
Volume : 17
Issue : 13
First Page : 3630
Last Page : 3635
Authors : Filzen GF, Bratton L, Cheng XM, Erasga N, Geyer A, Lee C, Lu G, Pulaski J, Sorenson RJ, Unangst PC, Trivedi BK, Xu X.
Abstract : Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
|
Agonist activity at human PPARdelta in HepG2 cells by GAL4-luciferase reporter gene assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and SAR of selective benzothiophene, benzofuran, and indole-based peroxisome proliferator-activated receptor delta agonists.
Year : 2007
Volume : 17
Issue : 13
First Page : 3630
Last Page : 3635
Authors : Filzen GF, Bratton L, Cheng XM, Erasga N, Geyer A, Lee C, Lu G, Pulaski J, Sorenson RJ, Unangst PC, Trivedi BK, Xu X.
Abstract : Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
|
Agonist activity at human PPARdelta by transactivation assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel selective PPARdelta agonists: optimization of activity by modification of alkynylallylic moiety.
Year : 2007
Volume : 17
Issue : 15
First Page : 4144
Last Page : 4149
Authors : Havranek M, Sauerberg P, Mogensen JP, Kratina P, Jeppesen CB, Pettersson I, Pihera P.
Abstract : Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARdelta activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARdelta potency of 0.13 microM, which is 50-fold more potent than compound 5.
|
Agonist activity at human PPARdelta receptor expressed in HEK293 cells by GAL4 transactivation assay
|
Homo sapiens
|
85.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenylpropanoic acid derivatives bearing a benzothiazole ring as PPARdelta-selective agonists.
Year : 2007
Volume : 17
Issue : 15
First Page : 4351
Last Page : 4357
Authors : Fujieda H, Usui S, Suzuki T, Nakagawa H, Ogura M, Makishima M, Miyata N.
Abstract : To find novel PPARdelta-selective agonists, we designed and synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazoles. Optimization of this series led to the identification of a potent and selective PPARdelta agonist 17. Molecular modeling suggested that compound 17 occupies the Y-shaped pocket of PPARdelta appropriately.
|
Agonist activity at human PPARdelta by transactivation assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design of a partial PPARdelta agonist.
Year : 2007
Volume : 17
Issue : 16
First Page : 4625
Last Page : 4629
Authors : Pettersson I, Ebdrup S, Havranek M, Pihera P, Korínek M, Mogensen JP, Jeppesen CB, Johansson E, Sauerberg P.
Abstract : Structure based ligand design was used in order to design a partial agonist for the PPARdelta receptor. The maximum activation in the transactivation assay was reduced from 87% to 39%. The crystal structure of the ligand binding domain of the PPARdelta receptor in complex with compound 2 was determined in order to understand the structural changes which gave rise to the decrease in maximum activation.
|
Displacement of [3H]GW 2433 from human PPARdelta by competition-binding assay
|
Homo sapiens
|
5.012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel class of PPARdelta partial agonists.
Year : 2008
Volume : 18
Issue : 18
First Page : 5018
Last Page : 5022
Authors : Shearer BG, Patel HS, Billin AN, Way JM, Winegar DA, Lambert MH, Xu RX, Leesnitzer LM, Merrihew RV, Huet S, Willson TM.
Abstract : Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells.
|
Agonist activity at human PPARdelta by Gal4 chimera cell-based reporter assay
|
Homo sapiens
|
3.162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel class of PPARdelta partial agonists.
Year : 2008
Volume : 18
Issue : 18
First Page : 5018
Last Page : 5022
Authors : Shearer BG, Patel HS, Billin AN, Way JM, Winegar DA, Lambert MH, Xu RX, Leesnitzer LM, Merrihew RV, Huet S, Willson TM.
Abstract : Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells.
|
Agonist activity at PPARdelta ligand binding domain expressed in human HeLa cells co-transfected with Gal4-DBD assessed as transcriptional activation by Gal4 response element-driven luciferase reporter gene assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective, potent PPARgamma agonists with cyclopentenone core structure.
Year : 2009
Volume : 19
Issue : 7
First Page : 1883
Last Page : 1886
Authors : Otero MP, Pérez Santín E, Rodríguez-Barrios F, Vaz B, de Lera AR.
Abstract : A series of analogues of the PPARgamma ligand 15-deoxy-Delta(12,14)-PGJ(2) have been synthesized by functionalization of a 5-alkyl-4-hydroxycyclopentenone core structure obtained by Piancatelli rearrangement of precursor furylcarbinol. Transient transactivation assays indicate that analogues 18 and 20 are selective nanomolar agonists of PPARgamma. This subtype selectivity is lost in derivatives (23, 24) with an alkynyl (oct-1-yn) chain at the C3 position, although the cyclopentenone derivative with cis relative configuration (23) showed greater affinity for PPARalpha.
|
Antagonist activity at human PPARdelta ligand binding domain-mediated transcriptional activity in CV1 cells by Gal4 chimera reporter assay
|
Homo sapiens
|
125.89
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist.
Year : 2010
Volume : 53
Issue : 4
First Page : 1857
Last Page : 1861
Authors : Shearer BG, Wiethe RW, Ashe A, Billin AN, Way JM, Stanley TB, Wagner CD, Xu RX, Leesnitzer LM, Merrihew RV, Shearer TW, Jeune MR, Ulrich JC, Willson TM.
Abstract : 4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.
|
Antagonist activity at human PPARdelta ligand binding domain-mediated transcriptional activity in CV1 cells by Gal4 chimera reporter assay relative to control
|
Homo sapiens
|
94.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist.
Year : 2010
Volume : 53
Issue : 4
First Page : 1857
Last Page : 1861
Authors : Shearer BG, Wiethe RW, Ashe A, Billin AN, Way JM, Stanley TB, Wagner CD, Xu RX, Leesnitzer LM, Merrihew RV, Shearer TW, Jeune MR, Ulrich JC, Willson TM.
Abstract : 4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.
|
Agonist activity at human PPARdelta ligand binding domain expressed in human 293T cells co-transfected with Gal4-DBD by luciferase transactivation assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.
Year : 2010
Volume : 53
Issue : 1
First Page : 77
Last Page : 105
Authors : Epple R, Cow C, Xie Y, Azimioara M, Russo R, Wang X, Wityak J, Karanewsky DS, Tuntland T, Nguyêñ-Trân VT, Cuc Ngo C, Huang D, Saez E, Spalding T, Gerken A, Iskandar M, Seidel HM, Tian SS.
Abstract : The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.
|
Agonist activity at human PPARdelta ligand binding domain by FRET assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.
Year : 2010
Volume : 53
Issue : 1
First Page : 77
Last Page : 105
Authors : Epple R, Cow C, Xie Y, Azimioara M, Russo R, Wang X, Wityak J, Karanewsky DS, Tuntland T, Nguyêñ-Trân VT, Cuc Ngo C, Huang D, Saez E, Spalding T, Gerken A, Iskandar M, Seidel HM, Tian SS.
Abstract : The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.
|
Agonist activity at mouse PPARdelta by FRET assay
|
Mus musculus
|
77.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.
Year : 2010
Volume : 53
Issue : 1
First Page : 77
Last Page : 105
Authors : Epple R, Cow C, Xie Y, Azimioara M, Russo R, Wang X, Wityak J, Karanewsky DS, Tuntland T, Nguyêñ-Trân VT, Cuc Ngo C, Huang D, Saez E, Spalding T, Gerken A, Iskandar M, Seidel HM, Tian SS.
Abstract : The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.
|
Induction of [14C]-oleic acid oxidation in human differentiated skeletal muscle cells assessed as accumulation of oxidized [14C]-oleic acid after 4 hrs by by liquid scintillation counting
|
Homo sapiens
|
0.07
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and dual PPARalpha/delta agonist effects of 1,4-disubstituted 1,2,3-triazole analogues of GW 501516.
Year : 2010
Volume : 45
Issue : 7
First Page : 3047
Last Page : 3055
Authors : Ciocoiu CC, Nikolić N, Nguyen HH, Thoresen GH, Aasen AJ, Hansen TV.
Abstract : Ten 1,4-disubstituted 1,2,3-triazoles 2a-2j were prepared and tested for their ability to increase oleic acid oxidation in human myotubes using a high-throughput multiwell assay. Compounds 2e (2-{4-[(1-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) and 2i (2-{4-[(1-(3-chloro-4-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methylthio]-2-methylphenoxy}acetic acid) exhibited potent agonist activities. Compounds 2e and 2i also exhibited powerful agonist effects for both PPARalpha and PPARdelta in a luciferase-based assay. Consequently, these triazoles can be categorized as dual PPAR agonists.
|
Agonist activity at Gal4-fused human PPARdelta DNA binding domain expressed in HEK293 cells by luciferase reporter gene assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists.
Year : 2011
Volume : 21
Issue : 1
First Page : 492
Last Page : 496
Authors : Luckhurst CA, Stein LA, Furber M, Webb N, Ratcliffe MJ, Allenby G, Botterell S, Tomlinson W, Martin B, Walding A.
Abstract : Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes.
|
Transactivation of Gal4-fused human PPARalpha DNA binding domain expressed in african green monkey CV1 cells by luciferase reporter gene assay
|
Homo sapiens
|
990.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a novel human PPARδ selective agonist and its stimulatory effect on oligodendrocyte differentiation.
Year : 2011
Volume : 21
Issue : 1
First Page : 240
Last Page : 244
Authors : Sakuma S, Endo T, Kanda T, Nakamura H, Yamasaki S, Yamakawa T.
Abstract : We successfully synthesized a novel peroxisome proliferator-activated receptor (PPAR)δ selective agonist, namely, compound 20, with a characteristic benzisoxazole ring. Compound 20 exhibited potent human PPARδ transactivation activity and high δ selectivity. Further, it stimulated differentiation of primary oligodendrocyte precursor cells in vitro, indicating that it may be an effective drug in the treatment of demyelinating disorders such as multiple sclerosis.
|
Transactivation of Gal4-fused human PPARdelta DNA binding domain expressed in african green monkey CV1 cells by luciferase reporter gene assay
|
Homo sapiens
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a novel human PPARδ selective agonist and its stimulatory effect on oligodendrocyte differentiation.
Year : 2011
Volume : 21
Issue : 1
First Page : 240
Last Page : 244
Authors : Sakuma S, Endo T, Kanda T, Nakamura H, Yamasaki S, Yamakawa T.
Abstract : We successfully synthesized a novel peroxisome proliferator-activated receptor (PPAR)δ selective agonist, namely, compound 20, with a characteristic benzisoxazole ring. Compound 20 exhibited potent human PPARδ transactivation activity and high δ selectivity. Further, it stimulated differentiation of primary oligodendrocyte precursor cells in vitro, indicating that it may be an effective drug in the treatment of demyelinating disorders such as multiple sclerosis.
|
Agonist activity at human PPARgamma expressed in HepG2 cells co-transfected with PPRE3-TK-luc assessed as beta-galactosidase activity after 20 to 22 hrs by luciferase based transactivation assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.
Year : 2011
Volume : 19
Issue : 2
First Page : 771
Last Page : 782
Authors : Makadia P, Shah SR, Pingali H, Zaware P, Patel D, Pola S, Thube B, Priyadarshini P, Suthar D, Shah M, Giri S, Trivedi C, Jain M, Patel P, Bahekar R.
Abstract : A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.
|
Agonist activity at human PPARdelta expressed in HepG2 cells co-transfected with PPRE3-TK-luc assessed as beta-galactosidase activity after 20 to 22 hrs by luciferase based transactivation assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Effect of structurally constrained oxime-ether linker on PPAR subtype selectivity: Discovery of a novel and potent series of PPAR-pan agonists.
Year : 2011
Volume : 19
Issue : 2
First Page : 771
Last Page : 782
Authors : Makadia P, Shah SR, Pingali H, Zaware P, Patel D, Pola S, Thube B, Priyadarshini P, Suthar D, Shah M, Giri S, Trivedi C, Jain M, Patel P, Bahekar R.
Abstract : A novel series of thaizole and oxazole containing phenoxy acetic acid derivatives is reported as PPAR-pan agonists. Incorporation of structurally constrained oxime-ether based linker in the chemotype of a potent PPARδ selective agonist GW-501516 was adapted as designing strategy. In vitro, selected test compounds 12a, 12c, 17a and 18a showed PPAR-pan agonists activities and among these four compounds tested, 12a emerged as highly potent and efficacious compound, while 17a exhibited moderate and balanced PPAR-pan agonistic activity. In vivo, selected test compounds 12a and 17a exhibited significant anti-hyperglycemic and anti-hyperlipidemic activities in relevant animal models. These results support our hypothesis that the introduction of structurally constrained oxime-ether linker between lipophilic tail and acidic head plays an important role in modulating subtype selectivity and subsequently led to the discovery of potent PPAR-pan agonists.
|
Displacement of [3H]GW 2433 from human PPARdelta by scintillation proximity assay
|
Homo sapiens
|
5.012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenoxyacetic acids as PPARδ partial agonists: synthesis, optimization, and in vivo efficacy.
Year : 2011
Volume : 21
Issue : 8
First Page : 2345
Last Page : 2350
Authors : Evans KA, Shearer BG, Wisnoski DD, Shi D, Sparks SM, Sternbach DD, Winegar DA, Billin AN, Britt C, Way JM, Epperly AH, Leesnitzer LM, Merrihew RV, Xu RX, Lambert MH, Jin J.
Abstract : A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
|
Partial agonist activity at human PPARdelta expressed in african green monkey CV1 cells transfected with Gal4 assessed as beta-galactosidase activity by transactivation assay
|
Homo sapiens
|
3.162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenoxyacetic acids as PPARδ partial agonists: synthesis, optimization, and in vivo efficacy.
Year : 2011
Volume : 21
Issue : 8
First Page : 2345
Last Page : 2350
Authors : Evans KA, Shearer BG, Wisnoski DD, Shi D, Sparks SM, Sternbach DD, Winegar DA, Billin AN, Britt C, Way JM, Epperly AH, Leesnitzer LM, Merrihew RV, Xu RX, Lambert MH, Jin J.
Abstract : A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
|
Agonist activity at human PPARalpha-LBD expressed in CV1 cells co-transfected with Gal4 after 40 hrs by luciferase based transactivation assay
|
Homo sapiens
|
990.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Biological evaluation of novel benzisoxazole derivatives as PPARδ agonists.
Year : 2011
Volume : 19
Issue : 10
First Page : 3255
Last Page : 3264
Authors : Sakuma S, Endo T, Kanda T, Nakamura H, Yamasaki S, Yamakawa T.
Abstract : We discovered novel peroxisome proliferator-activated receptor δ agonists with a characteristic benzisoxazole ring. Compound 5 exhibited potent human PPARδ transactivation activity. Furthermore, it stimulated the differentiation of oligodendrocyte precursor cells in vitro. This indicates that this potential drug may be effective for the treatment of demyelinating disorders such as multiple sclerosis.
|
Agonist activity at human PPARdelta-LBD expressed in CV1 cells co-transfected with Gal4 after 40 hrs by luciferase based transactivation assay
|
Homo sapiens
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Biological evaluation of novel benzisoxazole derivatives as PPARδ agonists.
Year : 2011
Volume : 19
Issue : 10
First Page : 3255
Last Page : 3264
Authors : Sakuma S, Endo T, Kanda T, Nakamura H, Yamasaki S, Yamakawa T.
Abstract : We discovered novel peroxisome proliferator-activated receptor δ agonists with a characteristic benzisoxazole ring. Compound 5 exhibited potent human PPARδ transactivation activity. Furthermore, it stimulated the differentiation of oligodendrocyte precursor cells in vitro. This indicates that this potential drug may be effective for the treatment of demyelinating disorders such as multiple sclerosis.
|
Induction of [14C]oleic acid oxidation in a human myotubes after 4 days by beta liquid scintillation counting
|
Homo sapiens
|
0.03
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.
Year : 2011
Volume : 19
Issue : 23
First Page : 6982
Last Page : 6988
Authors : Ciocoiu CC, Ravna AW, Sylte I, Rustan AC, Hansen TV.
Abstract : (±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARδ receptor with similar binding energies.
|
Agonist activity at human PPARgamma ligand binding domain expressed in COS-1 cells after 24 hrs by luciferase reporter gene-based luminometric analysis
|
Homo sapiens
|
912.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.
Year : 2011
Volume : 19
Issue : 23
First Page : 6982
Last Page : 6988
Authors : Ciocoiu CC, Ravna AW, Sylte I, Rustan AC, Hansen TV.
Abstract : (±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARδ receptor with similar binding energies.
|
Agonist activity at human PPARdelta ligand binding domain expressed in COS-1 cells after 24 hrs by luciferase reporter gene-based luminometric analysis
|
Homo sapiens
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516.
Year : 2011
Volume : 19
Issue : 23
First Page : 6982
Last Page : 6988
Authors : Ciocoiu CC, Ravna AW, Sylte I, Rustan AC, Hansen TV.
Abstract : (±)-2-Fluoro-2-(2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methyl)thio)phenoxy)acetic acid (2a) has been prepared and subjected to biological testing against all three subtypes of the PPARs. This compound exhibited agonist effects with EC(50) values of 560 and 55 nM against PPARα and PPARδ, respectively, in a luciferase assay. Moreover, compound (±)-2a also exhibited potent ability to induce oleic acid oxidation in a human myotube cell assay with EC(50)=3.7 nM. Compound (±)-2a can be classified as a dual PPARα/δ agonist with a 10-fold higher potency against the PPARδ receptor than against the PPARα receptor. Molecular modeling studies revealed that both enantiomers of 2a bind to the PPARδ receptor with similar binding energies.
|
Transactivation of human PPARdelta expressed in african green monkey CV1 cells by luciferase reporter gene assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Total synthesis and dual PPARα/γ agonist effects of amorphastilbol and its synthetic derivatives.
Year : 2012
Volume : 22
Issue : 12
First Page : 4122
Last Page : 4126
Authors : Kim T, Lee W, Jeong KH, Song JH, Park SH, Choi P, Kim SN, Lee S, Ham J.
Abstract : Amorphastilbol (APH-1), isolated from a Robinia pseudoacacia var. umbraculifer [corrected] seed extract, is a biologically interesting natural trans-stilbene compound with dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist activity. After total synthesis of APH-1 and its derivatives by Pd-catalyzed Suzuki-Miyaura cross-coupling of a common (E)-styryl bromide intermediate and various aromatic trifluoroborate compounds, we biologically evaluated APH-2-APH-12 for PPAR agonist activity. APH-4 and APH-11 were effective PPARα/γ transcriptional activators, compared with APH-1. Therefore, we suggest that APH-4 and APH-11 are novel dual PPARα/γ agonists and are potentially useful for treating type 2 diabetes by enhancing glucose and lipid metabolism.
|
Transactivation activity at human PPARalpha expressed in african green monkey CV1 cells after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
229.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo.
Year : 2012
Volume : 53
First Page : 190
Last Page : 202
Authors : Ham J, Hwang H, Kim E, Kim JA, Cho SJ, Ko J, Lee W, Lee J, Holla H, Banerjee J, Kim S, Yang I, Lee HJ, Shin K, Choi H, Nam SJ, Tak J, Hahn D, Oh T, Won DH, Lee TG, Choi J, Park MS, Seok C, Chin J, Kang H.
Abstract : We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARδ agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. The PPARδ ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy.
|
Transactivation activity at human PPARdelta expressed in african green monkey CV1 cells after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
2.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo.
Year : 2012
Volume : 53
First Page : 190
Last Page : 202
Authors : Ham J, Hwang H, Kim E, Kim JA, Cho SJ, Ko J, Lee W, Lee J, Holla H, Banerjee J, Kim S, Yang I, Lee HJ, Shin K, Choi H, Nam SJ, Tak J, Hahn D, Oh T, Won DH, Lee TG, Choi J, Park MS, Seok C, Chin J, Kang H.
Abstract : We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARδ agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. The PPARδ ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy.
|
Binding affinity at human GST-tagged PPARdelta ligand binding domain after 1 hr by time-resolved FRET analysis
|
Homo sapiens
|
24.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery, design and synthesis of Y-shaped peroxisome proliferator-activated receptor δ agonists as potent anti-obesity agents in vivo.
Year : 2012
Volume : 53
First Page : 190
Last Page : 202
Authors : Ham J, Hwang H, Kim E, Kim JA, Cho SJ, Ko J, Lee W, Lee J, Holla H, Banerjee J, Kim S, Yang I, Lee HJ, Shin K, Choi H, Nam SJ, Tak J, Hahn D, Oh T, Won DH, Lee TG, Choi J, Park MS, Seok C, Chin J, Kang H.
Abstract : We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARδ agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. The PPARδ ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy.
|
Agonist activity at PPARdelta
|
None
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Activity landscape modeling of PPAR ligands with dual-activity difference maps.
Year : 2012
Volume : 20
Issue : 11
First Page : 3523
Last Page : 3532
Authors : Méndez-Lucio O, Pérez-Villanueva J, Castillo R, Medina-Franco JL.
Abstract : Activation of peroxisome proliferator-activated receptor (PPAR) subtypes offers a promising strategy for the treatment of diabetes mellitus and metabolic diseases. Selective and dual PPAR agonists have been developed and the systematic characterization of their structure-activity relationships (SAR) is of major significance. Herein, we report a systematic description of the SAR of 168 compounds screened against the three PPAR subtypes using the principles of activity landscape modeling. As part of our effort to develop and apply chemoinformatic tools to navigate through activity landscapes, we employed consensus dual-activity difference maps recently reported. The analysis is based on pairwise relationships of potency difference and structure-similarity which were calculated from the combination of four different 2D and 3D structure representations. Dual-activity difference maps uncovered regions in the landscape with similar SAR for two or three receptor subtypes as well as regions with inverse SAR, that is, changes in structure that increase activity for one subtype but decrease activity for the other subtype. Analysis of pairs of compounds with high structure similarity revealed the presence of single-, dual-, and 'pan-receptor' activity cliffs, that is, small changes in structure with high changes in potency for one, two, or three receptor subtypes, respectively. Single-, dual-, and pan-receptor scaffold hops are also discussed. The analysis of the chemical structures of selected data points reported in this paper points to specific structural features that are helpful for the design of new PPAR agonists. The approach presented in this work is general and can be extended to analyze larger data sets.
|
Agonist activity at human PPARbeta expressed in HEK293 cells by luciferase reporter gene assay
|
Homo sapiens
|
0.18
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt.
Year : 2014
Volume : 24
Issue : 22
First Page : 5265
Last Page : 5267
Authors : Gege C, Schlüter T, Hoffmann T.
Abstract : Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORβ. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORγt and RORβ devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORβ and its biology.
|
Agonist activity at pSG5-Gal4-tagged human PPAR-beta/delta ligand binding domain expressed in COS1 cells assessed as receptor activation incubated for 19 hrs by pGL3-5XUAS-SV40 luciferase reporter gene assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618.
Year : 2015
Volume : 94
First Page : 229
Last Page : 236
Authors : Kaupang Å, Paulsen SM, Steindal CC, Ravna AW, Sylte I, Halvorsen TG, Thoresen GH, Hansen TV.
Abstract : 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.
|
Agonist activity at GAL4-tagged human PPARdelta ligand binding domain chimeric receptor expressed in HEK293 cells after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
5.9
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel acetyl-CoA carboxylase 2 (ACC2) inhibitors with peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonistic activity.
Year : 2016
Volume : 24
Issue : 21
First Page : 5258
Last Page : 5269
Authors : Okazaki S, Noguchi-Yachide T, Sakai T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi T.
Abstract : Acetyl-CoA carboxylases (ACCs) catalyze a critical step in de novo lipogenesis, and are considered as promising targets for treatment of obesity, dyslipidemia and type 2 diabetes mellitus. On the other hand, peroxisome proliferator-activated receptors (PPARs) are well-established therapeutic targets for these metabolic syndrome-related diseases. Therefore, we considered that dual modulators of ACC and PPARs would be promising candidates as therapeutic agents. Here, we designed a series of acetamides based on the molecular similarity between ACC inhibitors and PPAR agonists. Screening of the synthesized compounds identified N-(1-(3-(4-phenoxyphenyl)-1,2,4-oxadiazol-5-yl)ethyl)acetamides as novel ACC2 inhibitors with PPARα/PPARδ dual agonistic activity. Structure-activity relationship studies and further structural elaboration afforded compounds with distinct activity profiles. Our findings should be helpful for the discovery of candidate agents with an appropriate balance of ACC-inhibitory and PPAR-activating activities for therapeutic lipid control.
|
Displacement of Fluormone-Pan-PPAR Green from human GST-tagged PPARdelta LBD by TR-FRET assay
|
Homo sapiens
|
0.048
nM
|
|
Journal : J Med Chem
Title : Polypharmacology of N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) and Related A3 Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential.
Year : 2017
Volume : 60
Issue : 17
First Page : 7459
Last Page : 7475
Authors : Yu J, Ahn S, Kim HJ, Lee M, Ahn S, Kim J, Jin SH, Lee E, Kim G, Cheong JH, Jacobson KA, Jeong LS, Noh M.
Abstract : A3 adenosine receptor (AR) ligands including A3 AR agonist, N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (1a, IB-MECA) were examined for adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs). In this model, 1a significantly increased adiponectin production, which is associated with improved insulin sensitivity. However, A3 AR antagonists also promoted adiponectin production in hBM-MSCs, indicating that the A3 AR pathway may not be directly involved in the adiponectin promoting activity. In a target deconvolution study, their adiponectin-promoting activity was significantly correlated to their binding activity to both peroxisome proliferator activated receptor (PPAR) γ and PPARδ. They functioned as both PPARγ partial agonists and PPARδ antagonists. In the diabetic mouse model, 1a and its structural analogues A3 AR antagonists significantly decreased the serum levels of glucose and triglyceride, supporting their antidiabetic potential. These findings indicate that the polypharmacophore of these compounds may provide therapeutic insight into their multipotent efficacy against various human diseases.
|
Agonist activity at GAL4N fused human PPARdelta LBD expressed in HEK293 cells co-expressing TK-MH100x4-Luc after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
4.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists.
Year : 2017
Volume : 27
Issue : 14
First Page : 3131
Last Page : 3134
Authors : Shioi R, Okazaki S, Noguchi-Yachide T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi T.
Abstract : Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring ("fragment a"). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists.
|
Transactivation of GAL4-fused human PPARdelta LBD expressed in African green monkey CV1 cells after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
2.6
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulator demonstrates improved safety profile compared to GW501516.
Year : 2018
Volume : 28
Issue : 3
First Page : 533
Last Page : 536
Authors : Lagu B, Kluge AF, Goddeeris MM, Tozzo E, Fredenburg RA, Chellur S, Senaiar RS, Jaleel M, Babu DRK, Tiwari NK, Takahashi T, Patane MA.
Abstract : Compound 1 regulates significantly fewer genes than the PPARδ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns.
|
Transactivation of mouse PPARdelta by cell-based luciferase reporter gene assay
|
Mus musculus
|
70.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Highly selective peroxisome proliferator-activated receptor δ (PPARδ) modulator demonstrates improved safety profile compared to GW501516.
Year : 2018
Volume : 28
Issue : 3
First Page : 533
Last Page : 536
Authors : Lagu B, Kluge AF, Goddeeris MM, Tozzo E, Fredenburg RA, Chellur S, Senaiar RS, Jaleel M, Babu DRK, Tiwari NK, Takahashi T, Patane MA.
Abstract : Compound 1 regulates significantly fewer genes than the PPARδ modulator, GW501516. Both compounds are efficacious in a thermal injury model of muscle regeneration. The restricted gene profile of 1 relative to GW501516 suggests that 1 may be pharmacoequivalent to GW501516 with fewer PPAR-related safety concerns.
|
Transactivation of human PPARdelta expressed in monkey CV-1 cells coexpressing TK-PPRE-Luc after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor δ agonist.
Year : 2018
Volume : 26
Issue : 15
First Page : 4382
Last Page : 4389
Authors : Kim DS, Lee J, Londhe AM, Kadayat TM, Joo J, Hwang H, Kim KH, Pae AN, Chin J, Cho SJ, Kang H.
Abstract : In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.
|
Transactivation of human PPARalpha expressed in monkey CV-1 cells coexpressing TK-PPRE-Luc after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of an orally available "Y"-shaped biaryl peroxisome proliferator-activated receptor δ agonist.
Year : 2018
Volume : 26
Issue : 15
First Page : 4382
Last Page : 4389
Authors : Kim DS, Lee J, Londhe AM, Kadayat TM, Joo J, Hwang H, Kim KH, Pae AN, Chin J, Cho SJ, Kang H.
Abstract : In this study, we designed and synthesized several novel "Y"-shaped biaryl PPARδ agonists. Structure-activity relationship (SAR) studies demonstrated that compound 3a was the most active agonist with an EC50 of 2.6 nM. We also synthesized and evaluated enantiospecific R and S isomers of compound 3a to confirm that R isomer (EC50 = 0.7 nM) shows much more potent activity than S isomer (EC50 = 6.1 nM). Molecular docking studies between the PPAR ligand binding domain and enantiospecific R and S isomers of compound 3a were performed. In vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) and in vivo PK profiles show that compound 3a possesses superior drug-like properties including good bioavailability. Our overall results clearly demonstrate that this orally administrable PPARδ agonist 3a is a viable drug candidate for the treatment of various PPARδ-related disorders.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
1.94
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Agonist activity at N-terminal Gal4 fused human PPARdelta LBD transfected in HEK293 cells after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
5.9
nM
|
|
Journal : Bioorg Med Chem
Title : Structure-activity relationship studies of non-carboxylic acid peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists.
Year : 2016
Volume : 24
Issue : 21
First Page : 5455
Last Page : 5461
Authors : Okazaki S, Shioi R, Noguchi-Yachide T, Ishikawa M, Makishima M, Hashimoto Y, Yamaguchi T.
Abstract : The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that contribute to the regulation of lipid, glucose and cholesterol homeostases. They are considered as therapeutic targets for metabolic diseases such as dyslipidemia and type 2 diabetes mellitus. Various PPAR agonists have been developed, but most of them contain a carboxylic acid (CA) or thiazolidinedione (TZD) moiety, which is essential for the activity. However, we recently discovered non-CA/non-TZD class PPARα/δ dual agonists having an acetamide structure. Here, we describe structure-activity relationship (SAR) studies of these novel acetamide-based PPARα/δ dual agonists. The SAR studies revealed that the acetamide functionality and adjacent methyl group contribute greatly to the agonistic activity. Compound (S)-10 was the most potent PPARα/δ dual agonist among the compounds synthesized (PPARα EC<sub>50</sub>=17nM, PPARδ EC<sub>50</sub>=23nM).
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.3
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
19.63
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.17
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.17
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Competitive binding affinity to GST-tagged human PPARdelta LBD incubated for 1 to 6 hrs by TR-FRET assay
|
Homo sapiens
|
1.4
nM
|
|
Journal : Bioorg Med Chem
Title : Selenium bioisosteric replacement of adenosine derivatives promoting adiponectin secretion increases the binding affinity to peroxisome proliferator-activated receptor δ.
Year : 2020
Volume : 28
Issue : 1
First Page : 115226
Last Page : 115226
Authors : An S, Yu J, Choi H, Ko H, Ahn S, Shin JC, Pyo JJ, Jeong LS, Noh M.
Abstract : N<sup>6</sup>-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (1a, IB-MECA) exhibited polypharmacological characteristics targeting A<sub>3</sub> adenosine receptor (AR), peroxisome proliferator-activated receptor (PPAR) γ, and PPARδ, simultaneously. The bioisosteric replacement of oxygen in 4'-oxoadenosines with selenium significantly increased the PPARδ-binding activity. 2-Chloro-N<sup>6</sup>-(3-iodobenzyl)-4'-selenoadenosine-5'-N-methyluronamide (3e) and related 4'-selenoadenosine derivatives significantly enhanced adiponectin biosynthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). The PPARδ-binding affinity, but not the A<sub>3</sub> AR binding affinity, of 4'-selenoadenosine derivatives correlated with their adiponectin secretion stimulation. Compared with the sugar ring of 4'-oxoadenosine, that of 4'-selenoadenosine was more favorable in forming the South sugar conformation. In the molecular docking simulation, the South sugar conformation of compound 3e formed additional hydrogen bonds inside the PPARδ ligand-binding pocket compared with the North conformation. Therefore, the sugar conformation of 4'-selenoadenosine PPAR modulators affects the ligand binding affinity against PPARδ.
|
Agonist activity at PPARdelta (unknown origin)
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Med Chem
Title : Targeting Peroxisome Proliferator-Activated Receptor Delta (PPARδ): A Medicinal Chemistry Perspective.
Year : 2020
Volume : 63
Issue : 18
First Page : 10109
Last Page : 10134
Authors : Kadayat TM, Shrestha A, Jeon YH, An H, Kim J, Cho SJ, Chin J.
Abstract : One of the three subtypes of the peroxisome proliferator-activated receptor (PPAR) functioning as a transcription factor is the PPARβ or PPARδ. PPARδ is crucial to pathophysiological processes, including metabolic disorders, liver diseases, and cardiovascular diseases. In the past, the clinical development of PPARδ-selective agonist drugs has been stalled due to potential safety-related issues. Despite the elusiveness of such a drug, efforts continue in developing drugs that target PPARδ due to advances in the knowledge of the PPARδ receptor's structure and functions. While several preclinical and clinical studies are reported on PPARδ agonists, there is limited data with no clinical evidence available for PPARδ-selective antagonists. In this review, we mainly focus on the challenges of PPARδ selectivity and the medicinal chemistry of most active agonists discovered by different pharmaceutical companies and institutes. With this in mind, we also provide an update on the development status of PPARδ agonists that are undergoing clinical trials and their therapeutic promise for the treatment of various diseases.
|
Binding affinity to PPARdelta (unknown origin) by TR-FRET assay
|
Homo sapiens
|
0.82
nM
|
|
Journal : Bioorg Med Chem
Title : 2-Phenyl-8-(1-phenylallyl)-chromenone compounds have a pan-PPAR modulator pharmacophore.
Year : 2019
Volume : 27
Issue : 13.0
First Page : 2948
Last Page : 2958
Authors : Ahn S,Kim J,An S,Pyo JJ,Jung D,Lee J,Hwang SY,Gong J,Shin I,Kim HP,Kim H,Noh M
Abstract : Adiponectin is an adipocytokine with insulin-sensitizing, anti-atherogenic, and anti-inflammatory properties. Adiponectin secretion-inducing compounds have therapeutic potential in a variety of metabolic diseases. Phenotypic screening led to the discovery that 5,7-dihydroxy-8-(1-(4-hydroxy-3-methoxyphenyl)allyl)-2-phenyl-4H-chromen-4-one (compound 1) had adiponectin secretion-inducing activity during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). Compound 1 was originally reported to be an anti-cancer chemical isolated from natural honeybee propolis, and its adiponectin secretion-inducing activity was found in non-cytotoxic concentrations. In a target identification study, compound 1 and its potent synthetic derivative compound 5 were shown to be novel pan-peroxisome proliferator-activator receptor (PPAR) modulators. Molecular docking models with PPARs have indicated that the binding modes of chromenone compounds preferentially interacted with the hydrophobic ligand binding pocket of PPARs. In addition, chromenone compounds have been shown to result in different phenotypic outcomes in the transcriptional regulation of lipid metabolic enzymes than those of selective PPAR mono-agonists for PPARα, PPARγ, and PPARδ. In line with the pharmacology of adiponectin and PPAR pan-modulators, compounds 1 and 5 may have diverse therapeutic potentials to treat cancer and metabolic diseases.
|
Binding affinity to PPAR-delta (unknown origin) by TR-FRET assay
|
Homo sapiens
|
6.08
nM
|
|
Journal : J Med Chem
Title : Discovery and Structure-Activity Relationships of Novel Template, Truncated 1'-Homologated Adenosine Derivatives as Pure Dual PPARγ/δ Modulators.
Year : 2020
Volume : 63
Issue : 24
First Page : 16012
Last Page : 16027
Authors : An S,Kim G,Kim HJ,Ahn S,Kim HY,Ko H,Hyun YE,Nguyen M,Jeong J,Liu Z,Han J,Choi H,Yu J,Kim JW,Lee HW,Jacobson KA,Cho WJ,Kim YM,Kang KW,Noh M,Jeong LS
Abstract : Following our report that A adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1'-homologated adenosine analogues 4a-4t, as dual PPARγ/δ modulators without AR binding. Removal of binding affinity to AAR was achieved by 1'-homologation, and PPARγ/δ dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPARγ/δ but lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγ affinity, indicating that the C2 position defines a pharmacophore for selective PPARγ ligand designs. PPARγ/δ dual modulators functioning as both PPARγ partial agonists and PPARδ antagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.
|
Agonist activity at PPARdelta (unknown origin)
|
Homo sapiens
|
0.5
nM
|
|
