|
Effective concentration for 50% enhancement of insulin-induced triglyceride accumulation in 3T3-L1 cells
|
Mus musculus
|
160.0
nM
|
|
Effective concentration for 50% enhancement of insulin-induced triglyceride accumulation in 3T3-L1 cells
|
Mus musculus
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Isoxazolidine-3,5-dione and noncyclic 1,3-dicarbonyl compounds as hypoglycemic agents.
Year : 1998
Volume : 41
Issue : 11
First Page : 1927
Last Page : 1933
Authors : Shinkai H, Onogi S, Tanaka M, Shibata T, Iwao M, Wakitani K, Uchida I.
Abstract : Isoxazolidine-3,5-dione 2 (JTT-501), one of the cyclic malonic acid derivatives, was found to decrease blood glucose at an oral dose of 38 mg/kg/day in KKAy mice and is currently undergoing evaluation in phase II clinical trials. Further studies on a series of malonic acids and related compounds showed that the 1,3-dicarbonyl structure was important for insulin-sensitizing activity. Dimethyl malonate 10, which was selected as a successor for 2, was the optimum compound in a series of 1,3-dicarbonyl compounds and was more potent than the corresponding thiazolidine-2,4-dione 1.
|
Agonist activity for Human PPAR gamma receptor in transcriptional activation assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : J. Med. Chem.
Title : The PPARs: from orphan receptors to drug discovery.
Year : 2000
Volume : 43
Issue : 4
First Page : 527
Last Page : 550
Authors : Willson TM, Brown PJ, Sternbach DD, Henke BR.
|
Agonist activity for murine PPAR gamma receptor in transcriptional activation assay
|
Mus musculus
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : The PPARs: from orphan receptors to drug discovery.
Year : 2000
Volume : 43
Issue : 4
First Page : 527
Last Page : 550
Authors : Willson TM, Brown PJ, Sternbach DD, Henke BR.
|
Maximal reporter activity against human Peroxisome proliferator activated receptor gamma Gal4 chimeric in transiently transfected CV-1 cells by functional assay.
|
None
|
580.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight.
Year : 2001
Volume : 11
Issue : 24
First Page : 3111
Last Page : 3113
Authors : Liu KG, Lambert MH, Ayscue AH, Henke BR, Leesnitzer LM, Oliver WR, Plunket KD, Xu HE, Sternbach DD, Willson TM.
Abstract : A series of PPARgamma agonists were synthesized from L-tyrosine that incorporated low molecular weight N-substituents. The most potent analogue, pyrrole (4e), demonstrated a K(i) of 6.9nM and an EC(50) of 4.7nM in PPARgamma binding and functional assays, respectively. Pyrrole (4e), which is readily synthesized from L-tyrosine methyl ester in four steps, also demonstrated in vivo activity in a rodent model of Type 2 diabetes.
|
In vitro transactivation of human Peroxisome proliferator activated receptor gamma
|
Homo sapiens
|
970.0
nM
|
|
Journal : J. Med. Chem.
Title : Large dimeric ligands with favorable pharmacokinetic properties and peroxisome proliferator-activated receptor agonist activity in vitro and in vivo.
Year : 2003
Volume : 46
Issue : 23
First Page : 4883
Last Page : 4894
Authors : Sauerberg P, Bury PS, Mogensen JP, Deussen HJ, Pettersson I, Fleckner J, Nehlin J, Frederiksen KS, Albrektsen T, Din N, Svensson LA, Ynddal L, Wulff EM, Jeppesen L.
Abstract : Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.
|
Binding affinity to human Peroxisome proliferator activated receptor gamma using scintillation proximity assay
|
None
|
630.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of L-tyrosine-based PPARgamma agonists with reduced molecular weight.
Year : 2001
Volume : 11
Issue : 24
First Page : 3111
Last Page : 3113
Authors : Liu KG, Lambert MH, Ayscue AH, Henke BR, Leesnitzer LM, Oliver WR, Plunket KD, Xu HE, Sternbach DD, Willson TM.
Abstract : A series of PPARgamma agonists were synthesized from L-tyrosine that incorporated low molecular weight N-substituents. The most potent analogue, pyrrole (4e), demonstrated a K(i) of 6.9nM and an EC(50) of 4.7nM in PPARgamma binding and functional assays, respectively. Pyrrole (4e), which is readily synthesized from L-tyrosine methyl ester in four steps, also demonstrated in vivo activity in a rodent model of Type 2 diabetes.
|
Activation of peroxisome proliferator activated receptor gamma measured by induction of 50% of maximum alkaline phosphatase activity, transfection assay in CV-1 cells
|
None
|
588.84
nM
|
|
Journal : J. Med. Chem.
Title : N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents.
Year : 1998
Volume : 41
Issue : 25
First Page : 5020
Last Page : 5036
Authors : Henke BR, Blanchard SG, Brackeen MF, Brown KK, Cobb JE, Collins JL, Harrington WW, Hashim MA, Hull-Ryde EA, Kaldor I, Kliewer SA, Lake DH, Leesnitzer LM, Lehmann JM, Lenhard JM, Orband-Miller LA, Miller JF, Mook RA, Noble SA, Oliver W, Parks DJ, Plunket KD, Szewczyk JR, Willson TM.
Abstract : We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-L-tyrosine derivatives which are potent, selective PPARgamma agonists. Through the use of in vitro PPARgamma binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)+ ++amin o)propionic acid (2) was identified as a structurally novel PPARgamma agonist. Structure-activity relationships identified the 2-aminobenzophenone moiety as a suitable isostere for the chemically labile enaminone moiety in compound 2, affording 2-((2-benzoylphenyl)amino)-3-(4-(benzyloxy)phenyl)propionic acid (9). Replacement of the benzyl group in 9 with substituents known to confer in vivo potency in the thiazolidinedione (TZD) class of antidiabetic agents provided a dramatic increase in the in vitro functional potency and affinity at PPARgamma, affording a series of potent and selective PPARgamma agonists exemplified by (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(methylpyridin-2-ylamino+ ++)ethoxy ]phenyl¿propionic acid (18), 3-¿4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propanoic acid (20). Compounds 18 and 20 show potent antihyperglycemic and antihyperlipidemic activity when given orally in two rodent models of type 2 diabetes. In addition, these analogues are readily prepared in chiral nonracemic fashion from L-tyrosine and do not show a propensity to undergo racemization in vitro. The increased potency of these PPARgamma agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.
|
Transcriptional activation of peroxisome proliferator activated receptor gamma
|
Homo sapiens
|
588.84
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of a novel series of indole-derived PPARgamma agonists.
Year : 1999
Volume : 9
Issue : 23
First Page : 3329
Last Page : 3334
Authors : Henke BR, Adkison KK, Blanchard SG, Leesnitzer LM, Mook RA, Plunket KD, Ray JA, Roberson C, Unwalla R, Willson TM.
Abstract : The synthesis and structure-activity relationships of a novel series of indole 5-carboxylic acids that bind and activate peroxisome proliferator-activated receptor gamma (PPARgamma) are reported. These new analogs are selective for PPARgamma vs the other PPAR subtypes, and the most potent compounds in this series are comparable to in vitro potencies at PPARgamma reported for the thiazolidinedione-based antidiabetic drugs currently in clinical use.
|
In vitro transcriptional activation of Peroxisome proliferator activated receptor gamma (PPAR) expressed in CV-1 cells
|
Mus musculus
|
690.0
nM
|
|
Journal : J. Med. Chem.
Title : The structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones.
Year : 1996
Volume : 39
Issue : 3
First Page : 665
Last Page : 668
Authors : Willson TM, Cobb JE, Cowan DJ, Wiethe RW, Correa ID, Prakash SR, Beck KD, Moore LB, Kliewer SA, Lehmann JM.
|
In vitro transactivation using receptor transactivation assay against hPPAR gamma
|
None
|
970.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel tricyclic-alpha-alkyloxyphenylpropionic acids: dual PPARalpha/gamma agonists with hypolipidemic and antidiabetic activity.
Year : 2002
Volume : 45
Issue : 4
First Page : 789
Last Page : 804
Authors : Sauerberg P, Pettersson I, Jeppesen L, Bury PS, Mogensen JP, Wassermann K, Brand CL, Sturis J, Wöldike HF, Fleckner J, Andersen AS, Mortensen SB, Svensson LA, Rasmussen HB, Lehmann SV, Polivka Z, Sindelar K, Panajotova V, Ynddal L, Wulff EM.
Abstract : Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.
|
Transactivation of PPARgamma in CV1 cells
|
Homo sapiens
|
550.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists.
Year : 2006
Volume : 49
Issue : 14
First Page : 4072
Last Page : 4084
Authors : Chittiboyina AG, Venkatraman MS, Mizuno CS, Desai PV, Patny A, Benson SC, Ho CI, Kurtz TW, Pershadsingh HA, Avery MA.
Abstract : A series of novel derivatives of potent antioxidant vitamin, alpha-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARgamma agonist activities. Compounds 9a and the water soluble analogue11e were found to be potent PPARgamma agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.
|
Displacement of [3H]rosiglitazone from PPAR gamma
|
None
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid derivatives as PPARgamma activators.
Year : 2007
Volume : 17
Issue : 16
First Page : 4613
Last Page : 4618
Authors : Kumar R, Mittal A, Ramachandran U.
Abstract : The design and synthesis of novel series of 6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (pyrimidone) derivatives that are high affinity ligands for peroxisome proliferators activated receptor gamma have been reported as a potential substitute of 2,4-thiazolidinedione head group. The FlexX docking and radioligand binding affinity of some promising compounds of this series is comparable to that of thiazolidinedione based antidiabetic drugs currently in clinical use.
|
Displacement of [3H]rosiglitazone from mouse PPARgamma receptor by scintillation proximation assay
|
Mus musculus
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New PPARgamma ligands based on barbituric acid: virtual screening, synthesis and receptor binding studies.
Year : 2008
Volume : 18
Issue : 18
First Page : 4959
Last Page : 4962
Authors : Sundriyal S, Viswanad B, Ramarao P, Chakraborti AK, Bharatam PV.
Abstract : A new series of PPARgamma ligands based on barbituric acid (BA) has been designed employing virtual screening and molecular docking approach. To validate the computational approach, designed molecules were synthesized and evaluated in in vitro radioligand binding studies. Out of the total 14 molecules, 6 were found to bind to the murine PPARgamma with IC(50) ranging from 0.1 to 2.5 microM as compared to reference standard, pioglitazone (IC(50)=0.7 microM).
|
Displacement of [3H]rosigliatzone from PPARgamma in rat adipocytes
|
Rattus norvegicus
|
700.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : New PPARgamma ligands based on 2-hydroxy-1,4-naphthoquinone: computer-aided design, synthesis, and receptor-binding studies.
Year : 2008
Volume : 18
Issue : 11
First Page : 3192
Last Page : 3195
Authors : Sundriyal S, Viswanad B, Bharathy E, Ramarao P, Chakraborti AK, Bharatam PV.
Abstract : FlexX-based molecular docking study was employed to identify 2-hydroxy-1,4-naphthoquinone as a new 'acidic head group' for the design of a novel series of PPARgamma ligands. To provide the proof of concept, designed molecules were synthesized and evaluated in a standard radioligand-binding assay. Out of eight molecules, four were found to bind to the murine PPARgamma with IC(50) ranging from 0.2 to 56.2 microM as compared to standard pioglitazone, with IC(50) of 0.7 microM.
|
Transactivation of human PPARgamma LBD expressed in african green monkey Cos7 cells co-transfected with fused GAL4-DBD after 14 hrs by Dual-Glo Luciferase reporter gene assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator.
Year : 2010
Volume : 20
Issue : 8
First Page : 2469
Last Page : 2473
Authors : Thieme TM, Steri R, Proschak E, Paulke A, Schneider G, Schubert-Zsilavecz M.
Abstract : Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in glucose and lipid homeostasis. PPARgamma agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPARgamma modulators (SPPARgammaMs) was developed, which are believed to show less side effects than full PPARgamma agonists. We have previously shown that alpha-substitution of pirinixic acid, a moderate agonist of PPARalpha and PPARgamma, leads to low micromolar active balanced dual agonists of PPARalpha and PPARgamma. Herein we present modifications of pirinixic acid leading to subtype-selective PPARgamma agonists and furthermore the development of a selective PPARgamma modulator guided by molecular docking studies.
|
Agonist activity at PPARgamma assessed as transcriptional activation
|
None
|
88.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel selective PPARgamma modulator from (-)-Cercosporamide derivatives.
Year : 2010
Volume : 20
Issue : 7
First Page : 2095
Last Page : 2098
Authors : Furukawa A, Arita T, Satoh S, Wakabayashi K, Hayashi S, Matsui Y, Araki K, Kuroha M, Ohsumi J.
Abstract : In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.
|
Activation of Gal4-tagged human PPARgamma expressed in CHO cells by luciferase reporter gene assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Characterization of new PPARgamma agonists: benzimidazole derivatives-importance of positions 5 and 6, and computational studies on the binding mode.
Year : 2010
Volume : 18
Issue : 16
First Page : 5885
Last Page : 5895
Authors : Goebel M, Wolber G, Markt P, Staels B, Unger T, Kintscher U, Gust R.
Abstract : In this and previous studies we investigated the importance of partial structures of Telmisartan on PPARgamma activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl)methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d]imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPARgammaDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARgamma activation. An enhanced effect on PPARgamma activation could be observed if lipophilic moieties are introduced in these positions. 4'-[(2-Propyl-1H-naphtho[2,3-d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC(50) of 0.26muM and the profile of a full agonist. Together with compounds of the former structure-activity relationship study (position 2-substituted benzimidazole derivatives 4a-4j), the binding mode of Telmisartan and its derivatives have been analyzed in 3D pharmacophore-driven docking experiments.
|
Inhibition of human recombinant MAO-B after 15 mins
|
Homo sapiens
|
298.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of novel monoamine oxidase B inhibitors by structure-based virtual screening.
Year : 2010
Volume : 20
Issue : 17
First Page : 5295
Last Page : 5298
Authors : Geldenhuys WJ, Darvesh AS, Funk MO, Van der Schyf CJ, Carroll RT.
Abstract : Parkinson's disease is a severe debilitating neurodegenerative disorder. Recently, it was shown that the peroxisome proliferating-activator receptor-gamma agonist pioglitazone protected mice from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity due to its ability to inhibit monoamine oxidase B (MAO-B). Docking studies were initiated to investigate pioglitazone's interactions within the substrate cavity of MAO-B. Modeling studies indicated that the thiazolidinedione (TZD) moiety was a likely candidate for its specificity to MAO-B. To explore this potential novel MAO-B scaffold, we performed a structure-based virtual screen to identify additional MAO-B inhibitors. Our search identified eight novel compounds containing the TZD-moiety that allowed for a limited study to identify structural requirements for binding to MAO-B. Inhibition assays identified two TZDs (A6355 and L136662) which were found to inhibit recombinant human MAO-B with IC(50) values of 82 and 195 nM, respectively.
|
Displacement of fluormone PPAR-green from N-terminal His-tagged human PPARgamma-LBD after 2 hrs by fluorescence polarization assay
|
Homo sapiens
|
855.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 1,3-Diphenyl-1H-pyrazole derivatives as a new series of potent PPARγ partial agonists.
Year : 2010
Volume : 18
Issue : 23
First Page : 8315
Last Page : 8323
Authors : Choi J, Park Y, Lee HS, Yang Y, Yoon S.
Abstract : A new series of PPARγ partial agonists, 1,3-diphenyl-1H-pyrazole derivatives, were identified using an improved virtual screening scheme combining ligand-centric and receptor-centric methods. An in vitro assay confirmed the nanomolar binding affinity of 1,3-diphenyl-1H-pyrazole derivatives such as SP3415. We also characterized the competitive antagonism of SP3415 against rosiglitazone at micromolar concentrations. They showed a PPARγ partial agonistic activity similar to that of a known PPARγ drug, pioglitazone, in a cell-based transactivation assay. Furthermore, the structure-activity relationships of the pyrazole derivatives were investigated through comparative molecular field analysis and binding mode analysis, which provided new insight concerning their partial agonistic effect on PPARγ.
|
Agonist activity at human PPARgamma ligand binding domain expressed in COS-1 cells co-transfected with Gal4 by luciferase reporter gene assay
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of a new class of benzoylpyrrole-based PPARα/γ activators.
Year : 2011
Volume : 21
Issue : 1
First Page : 220
Last Page : 224
Authors : Ushiroda K, Maruta K, Kitoh M, Iwai K, Nagamine J, Tsuchida A, Taiji M, Nagata R.
Abstract : Starting with a subtle blood glucose-lowering effect of a TGF-β inhibitor, we designed and synthesized a series of benzoylpyrrole-based carboxylic acids as PPARs activators. Among these compounds, 10sNa exhibited favorable blood glucose-lowering effect without body weight gain. We assume that the beneficial effect of 10sNa is attributed to not only its compound PPARα agonistic activity but also its PPARγ partial agonistic activity.
|
Partial agonist activity at human PPARgamma expressed in CHO cells co-transfected with Gal4-responsive luciferase reporter plasmid after 24 hrs by transactivation assay
|
Homo sapiens
|
390.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of novel benzoylazole-based PPAR α/γ activators.
Year : 2011
Volume : 21
Issue : 7
First Page : 1978
Last Page : 1982
Authors : Ushiroda K, Maruta K, Takazawa T, Nagano T, Taiji M, Kohno T, Sato Y, Horai S, Yanagi K, Nagata R.
Abstract : In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.
|
Antidiabetic effect in db/db mouse assessed as reduction in plasma glucose level at 30 mg/kg/day, po administered daily for 14 days
|
Mus musculus
|
46.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of novel benzoylazole-based PPAR α/γ activators.
Year : 2011
Volume : 21
Issue : 7
First Page : 1978
Last Page : 1982
Authors : Ushiroda K, Maruta K, Takazawa T, Nagano T, Taiji M, Kohno T, Sato Y, Horai S, Yanagi K, Nagata R.
Abstract : In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.
|
Antidiabetic effect in db/db mouse assessed as reduction in plasma triglyceride level at 30 mg/kg/day, po administered daily for 14 days
|
Mus musculus
|
69.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of novel benzoylazole-based PPAR α/γ activators.
Year : 2011
Volume : 21
Issue : 7
First Page : 1978
Last Page : 1982
Authors : Ushiroda K, Maruta K, Takazawa T, Nagano T, Taiji M, Kohno T, Sato Y, Horai S, Yanagi K, Nagata R.
Abstract : In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.
|
Antidiabetic effect in db/db mouse assessed as increase in HDL cholesterol level at 30 mg/kg/day, po administered daily for 14 days
|
Mus musculus
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of novel benzoylazole-based PPAR α/γ activators.
Year : 2011
Volume : 21
Issue : 7
First Page : 1978
Last Page : 1982
Authors : Ushiroda K, Maruta K, Takazawa T, Nagano T, Taiji M, Kohno T, Sato Y, Horai S, Yanagi K, Nagata R.
Abstract : In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.
|
Modulation of human PPARgamma-LBD expressed in african green monkey COS7 cells co-transfected with Gal4 assessed as activation of transactivation activity by luciferase assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : SAR studies of acidic dual γ-secretase/PPARγ modulators.
Year : 2011
Volume : 19
Issue : 18
First Page : 5372
Last Page : 5382
Authors : Hieke M, Ness J, Steri R, Greiner C, Werz O, Schubert-Zsilavecz M, Weggen S, Zettl H.
Abstract : A novel set of dual γ-secretase/PPARγ modulators characterized by a 2-benzyl hexanoic acid scaffold is presented. Synthetic efforts were focused on the variation of the substitution pattern of the central benzene. Finally, we obtained a new class of 2,5-disubstituted 2-benzylidene hexanoic acid derivatives, which act as dual γ-secretase/PPARγ modulators in the low micromolar range. We have explored broad SAR and successfully improved the dual pharmacological activity and the selectivity profile against potential off-targets such as NOTCH and COX. Compound 17 showed an IC(50) Aβ42=2.4 μM and an EC(50) PPARγ=7.2 μM and could be a valuable tool to further evaluate the concept of dual γ-secretase/PPARγ modulators in animal models of Alzheimer's disease.
|
DRUGMATRIX: Carbonic Anhydrase II enzyme inhibition (substrate: 4-Nitrophenyl acetate (4-NPA))
|
Homo sapiens
|
114.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Agonist activity at GAL4-tagged human PPARgamma ligand binding domain expressed in HepG2 cells assessed as transactivation after 20 hrs by beta-galactosidase reporter gene assay
|
Homo sapiens
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation and molecular investigation of fluorinated peroxisome proliferator-activated receptors α/γ dual agonists.
Year : 2012
Volume : 20
Issue : 6
First Page : 2141
Last Page : 2151
Authors : Fracchiolla G, Laghezza A, Piemontese L, Parente M, Lavecchia A, Pochetti G, Montanari R, Di Giovanni C, Carbonara G, Tortorella P, Novellino E, Loiodice F.
Abstract : PPARs are transcription factors that govern lipid and glucose homeostasis and play a central role in cardiovascular disease, obesity, and diabetes. Thus, there is significant interest in developing new agonists for these receptors. Given that the introduction of fluorine generally has a profound effect on the physical and/or biological properties of the target molecule, we synthesized a series of fluorinated analogs of the previously reported compound 2, some of which turned out to be remarkable PPARα and PPARγ dual agonists. Docking experiments were also carried out to gain insight into the interactions of the most active derivatives with both receptors.
|
Competitive inhibition of human MAOB expressed in Pichia pastoris
|
Homo sapiens
|
500.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Anti-Diabetes Drugs.
Year : 2012
Volume : 3
Issue : 1
First Page : 39
Last Page : 42
Authors : Binda C, Aldeco M, Geldenhuys WJ, Tortorici M, Mattevi A, Edmondson DE.
Abstract : The widely employed anti-diabetic drug pioglitazone (Actos) is shown to be a specific and reversible inhibitor of human monoamine oxidase B (MAO B). The crystal structure of the enzyme-inhibitor complex shows the R-enantiomer is bound with the thiazolidinedione ring near the flavin. The molecule occupies both substrate and entrance cavities of the active site establishing non-covalent interactions with the surrounding amino acids. These binding properties differentiate pioglitazone from the clinically used MAO inhibitors, which act through covalent inhibition mechanisms and do not exhibit a high degree of MAO A versus B selectivity. Rosiglitazone (Avandia) and troglitazone, other members of the glitazone class, are less selective in that they are weaker inhibitors of both MAO A and MAO B These results suggest that pioglitazone may have utility as a "re-purposed" neuro-protectant drug in retarding the progression of disease in Parkinson's patients. They also provide new insights for the development of reversible isoenzyme-specific MAO inhibitors.
|
TP_TRANSPORTER: inhibition of estrone-3-sulfate uptake (Estrone-3-sulfate: 9.2 nM) by Pioglitazone at a concentration of 10uM in OATP8-expressing Xenopus oocytes
|
Xenopus laevis
|
65.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity.
Year : 2004
Volume : 32
Issue : 1
First Page : 291
Last Page : 294
Authors : Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, Tamai I.
Abstract : Troglitazone is a thiazolidinedione insulin sensitizer drug that is metabolized mainly to a sulfate conjugate (M-1) in humans. It was reported to cause hepatotoxicity, although the cause has not been fully clarified. The objective of this study was to identify whether organic anion transporting polypeptide (OATP) transporters expressed at the basolateral membrane of human hepatocytes participate in troglitazone-associated hepatotoxicity. When OATP-B, OATP-C, or OATP8 was expressed in Xenopus oocytes, the transporter-mediated uptake into oocytes of troglitazone sulfate conjugate and the inhibitory effects of thiazolidinediones and the metabolites of troglitazone on estrone-3-sulfate transport were measured. M-1 was transported well by OATP-C but was not transported by OATP-B. OATP8 showed weak, but not statistically significant, transport of M-1. M-1 exhibited a strong inhibitory effect on estrone-3-sulfate transport by OATP-C and OATP8, suggesting a higher affinity than other thiazolidinediones and the metabolites of troglitazone, glucuronide conjugate and quinone metabolite. In conclusion, the sulfate conjugate of troglitazone has a higher affinity for OATPs than troglitazone itself or other metabolites. Since OATP transporters are important in the hepatic handling of bile acids, bilirubin, and other endogenous anionic compounds, M-1 may disturb the hepatic influx and efflux transport of these endogenous molecules across the basolateral membranes. Moreover, OATP-C may be involved in the hepatic toxicity of troglitazone through the inhibitory action of M-1.
|
TP_TRANSPORTER: inhibition of estrone-3-sulfate uptake (Estrone-3-sulfate: 9.2 nM) by Pioglitazone at a concentration of 10uM in OATP-C-expressing Xenopus oocytes
|
Xenopus laevis
|
70.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity.
Year : 2004
Volume : 32
Issue : 1
First Page : 291
Last Page : 294
Authors : Nozawa T, Sugiura S, Nakajima M, Goto A, Yokoi T, Nezu J, Tsuji A, Tamai I.
Abstract : Troglitazone is a thiazolidinedione insulin sensitizer drug that is metabolized mainly to a sulfate conjugate (M-1) in humans. It was reported to cause hepatotoxicity, although the cause has not been fully clarified. The objective of this study was to identify whether organic anion transporting polypeptide (OATP) transporters expressed at the basolateral membrane of human hepatocytes participate in troglitazone-associated hepatotoxicity. When OATP-B, OATP-C, or OATP8 was expressed in Xenopus oocytes, the transporter-mediated uptake into oocytes of troglitazone sulfate conjugate and the inhibitory effects of thiazolidinediones and the metabolites of troglitazone on estrone-3-sulfate transport were measured. M-1 was transported well by OATP-C but was not transported by OATP-B. OATP8 showed weak, but not statistically significant, transport of M-1. M-1 exhibited a strong inhibitory effect on estrone-3-sulfate transport by OATP-C and OATP8, suggesting a higher affinity than other thiazolidinediones and the metabolites of troglitazone, glucuronide conjugate and quinone metabolite. In conclusion, the sulfate conjugate of troglitazone has a higher affinity for OATPs than troglitazone itself or other metabolites. Since OATP transporters are important in the hepatic handling of bile acids, bilirubin, and other endogenous anionic compounds, M-1 may disturb the hepatic influx and efflux transport of these endogenous molecules across the basolateral membranes. Moreover, OATP-C may be involved in the hepatic toxicity of troglitazone through the inhibitory action of M-1.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
21.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
5.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-9.9
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Transactivation of GAL4-fused human PPARgamma ligand binding domain transfected in african green monkey COS7 cells by luciferase reporter gene assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Design and synthesis of dual modulators of soluble epoxide hydrolase and peroxisome proliferator-activated receptors.
Year : 2012
Volume : 55
Issue : 23
First Page : 10771
Last Page : 10775
Authors : la Buscató E, Blöcher R, Lamers C, Klingler FM, Hahn S, Steinhilber D, Schubert-Zsilavecz M, Proschak E.
Abstract : Metabolic syndrome is a complex condition which often requires the use of multiple medications as a treatment. The resulting problems of polypharmacy are increase in side effects, drug-drug interactions, and its high economic cost. Development of multitarget compounds is a promising strategy to avoid the complications arising from administration of multiple drugs. Modulators of peroxisome proliferator-activated receptors (PPARs) are established agents in the treatment of dyslipidaemia, hyperglycaemia, and insulin resistance. Inhibitors of soluble epoxide hydrolase (sEH) are under evaluation for their use in cardiovascular diseases. In the present study, a series of dual sEH/PPAR modulators containing a pyrrole acidic headgroup and a urea pharmacophore were designed, synthesized, and evaluated in vitro using recombinant enzyme and cell-based assays. Compounds with different activity profiles were obtained which could be used in the treatment of metabolic syndrome.
|
Transactivation of human GAL4-fused PPARgamma ligand binding domain transfected in HEK293 cells after 18 hrs by dual luciferase reporter gene assay
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs.
Year : 2012
Volume : 22
Issue : 24
First Page : 7662
Last Page : 7666
Authors : Giampietro L, D'Angelo A, Giancristofaro A, Ammazzalorso A, De Filippis B, Fantacuzzi M, Linciano P, Maccallini C, Amoroso R.
Abstract : In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARα or PPARγ, while others were identified as dual agonists PPARα/γ.
|
Transactivation activity at Homo sapiens (human) PPARgamma
|
Homo sapiens
|
600.0
nM
|
|
Journal : Med Chem Res
Title : Ligand-based in silico 3D-QSAR study of PPAR- agonists
Year : 2011
Volume : 20
Issue : 7
First Page : 1005
Last Page : 1014
Authors : Sonawane LV, Bari SB
|
Agonist activity at human PPARgamma expressed in HEK293 cells incubated for 18 hrs by luciferase reporter gene assay
|
Homo sapiens
|
210.0
nM
|
|
Journal : J. Nat. Prod.
Title : Polyyne hybrid compounds from Notopterygium incisum with peroxisome proliferator-activated receptor gamma agonistic effects.
Year : 2014
Volume : 77
Issue : 11
First Page : 2513
Last Page : 2521
Authors : Liu X, Kunert O, Blunder M, Fakhrudin N, Noha SM, Malainer C, Schinkovitz A, Heiss EH, Atanasov AG, Kollroser M, Schuster D, Dirsch VM, Bauer R.
Abstract : In the search for peroxisome proliferator-activated receptor gamma (PPARγ) active constituents from the roots and rhizomes of Notopterygium incisum, 11 new polyacetylene derivatives (1-11) were isolated. Their structures were elucidated by NMR and HRESIMS as new polyyne hybrid molecules of falcarindiol with sesquiterpenoid or phenylpropanoid moieties, named notoethers A-H (1-8) and notoincisols A-C (9-11), respectively. Notoincisol B (10) and notoincisol C (11) represent two new carbon skeletons. When tested for PPARγ activation in a luciferase reporter assay with HEK-293 cells, notoethers A-C (1-3), notoincisol A (9), and notoincisol B (10) showed promising agonistic activity (EC50 values of 1.7 to 2.3 μM). In addition, notoincisol A (9) exhibited inhibitory activity on NO production of stimulated RAW 264.7 macrophages.
|
Inhibition of human recombinant microsomal MAO-B expressed in Pichia pastoris incubated for 30 mins prior to substrate addition measured after 60 mins by MAO-Glo assay
|
Homo sapiens
|
270.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Inhibition of human recombinant soluble MAO-B expressed in Pichia pastoris incubated for 30 mins prior to substrate addition measured after 60 mins by MAO-Glo assay
|
Homo sapiens
|
199.4
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Reversible and irreversible small molecule inhibitors of monoamine oxidase B (MAO-B) investigated by biophysical techniques.
Year : 2015
Volume : 23
Issue : 4
First Page : 770
Last Page : 778
Authors : Rojas RJ, Edmondson DE, Almos T, Scott R, Massari ME.
Abstract : Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds. Described here is the development of such approaches for reversible and irreversible small molecule inhibitors of MAO-B. Investigation of soluble recombinant MAO-B revealed mechanism-based differences in the thermal shift and binding thermodynamic profiles of MAO-B inhibitors. Irreversible inhibitors demonstrated biphasic protein melt curves, large enthalpically favorable and entropically unfavorable binding, in contrast to reversible compounds, which were characterized by a dose-dependent increase in thermal stability and enthalpically-driven binding. The biophysical approaches described here aim to facilitate the discovery of next-generation MAO-B inhibitors.
|
Hypoglycemic effect in eight week old female db/db mouse assessed as reduction in blood glucose level at 30 mg/kg, intragastric for 1 week
|
Mus musculus
|
25.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of GY3-based derivatives for anti-type 2 diabetes activity.
Year : 2015
Volume : 25
Issue : 7
First Page : 1500
Last Page : 1505
Authors : Fan L, Wang J, Ma X, Xiao W, Li Z, Zhong G, Tang L, Wu H.
Abstract : A series of indole carboxylic acid derivatives were designed and synthesized. Their anti-type 2 diabetes activity was evaluated in HepG2 cell and db/db mice. The results showed that compounds 8c, 17a, 17b, 15a and 15b could significantly increase glucose consumption in HepG2 cell. Furthermore, compound 8c was able to lower the blood glucose level and induce less weight gain in db/db mice.
|
Hypoglycemic effect in eight week old female db/db mouse assessed as reduction in blood glucose level at 30 mg/kg, intragastric for 2 weeks
|
Mus musculus
|
30.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of GY3-based derivatives for anti-type 2 diabetes activity.
Year : 2015
Volume : 25
Issue : 7
First Page : 1500
Last Page : 1505
Authors : Fan L, Wang J, Ma X, Xiao W, Li Z, Zhong G, Tang L, Wu H.
Abstract : A series of indole carboxylic acid derivatives were designed and synthesized. Their anti-type 2 diabetes activity was evaluated in HepG2 cell and db/db mice. The results showed that compounds 8c, 17a, 17b, 15a and 15b could significantly increase glucose consumption in HepG2 cell. Furthermore, compound 8c was able to lower the blood glucose level and induce less weight gain in db/db mice.
|
Hypoglycemic effect in eight week old female db/db mouse assessed as reduction in blood glucose level at 30 mg/kg, intragastric for 3 weeks
|
Mus musculus
|
30.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of GY3-based derivatives for anti-type 2 diabetes activity.
Year : 2015
Volume : 25
Issue : 7
First Page : 1500
Last Page : 1505
Authors : Fan L, Wang J, Ma X, Xiao W, Li Z, Zhong G, Tang L, Wu H.
Abstract : A series of indole carboxylic acid derivatives were designed and synthesized. Their anti-type 2 diabetes activity was evaluated in HepG2 cell and db/db mice. The results showed that compounds 8c, 17a, 17b, 15a and 15b could significantly increase glucose consumption in HepG2 cell. Furthermore, compound 8c was able to lower the blood glucose level and induce less weight gain in db/db mice.
|
Inhibition of human BSEP expressed in plasma membrane vesicles of Sf21 cells assessed as inhibition of ATP-dependent [3H]taurocholate uptake
|
Homo sapiens
|
300.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans.
Year : 2012
Volume : 40
Issue : 1
First Page : 130
Last Page : 138
Authors : Dawson S, Stahl S, Paul N, Barber J, Kenna JG.
Abstract : Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.
|
Time dependent inhibition of CYP1A2 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2B6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
38.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C9 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C19 in human liver microsomes at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2D6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP3A4 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
61.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C8 (unknown origin) at 30 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Agonist activity at PPARgamma (unknown origin)
|
Homo sapiens
|
720.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists.
Year : 2015
Volume : 25
Issue : 15
First Page : 2907
Last Page : 2912
Authors : Fauber BP, Gobbi A, Robarge K, Zhou A, Barnard A, Cao J, Deng Y, Eidenschenk C, Everett C, Ganguli A, Hawkins J, Johnson AR, La H, Norman M, Salmon G, Summerhill S, Ouyang W, Tang W, Wong H.
Abstract : The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.
|
Transactivation of human PPARgamma expressed in African green monkey COS7 cells incubated overnight by dual-glo luciferase reporter gene assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor γ Modulators.
Year : 2016
Volume : 59
Issue : 1
First Page : 61
Last Page : 81
Authors : Blöcher R, Lamers C, Wittmann SK, Merk D, Hartmann M, Weizel L, Diehl O, Brüggerhoff A, Boß M, Kaiser A, Schader T, Göbel T, Grundmann M, Angioni C, Heering J, Geisslinger G, Wurglics M, Kostenis E, Brüne B, Steinhilber D, Schubert-Zsilavecz M, Kahnt AS, Proschak E.
Abstract : Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 μM/PPARγ EC50 = 0.3 μM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.
|
Antidiabetic activity in leptin receptor deficient db/db C57BL/KSJ mouse assessed as decrease in fasting blood glucose level administered for 15 consecutive days relative to control
|
Mus musculus
|
62.4
%
|
|
Journal : J Nat Prod
Title : Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.
Year : 2016
Volume : 79
Issue : 5
First Page : 1276
Last Page : 1284
Authors : Patel OP, Mishra A, Maurya R, Saini D, Pandey J, Taneja I, Raju KS, Kanojiya S, Shukla SK, Srivastava MN, Wahajuddin M, Tamrakar AK, Srivastava AK, Yadav PP.
Abstract : This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
|
Antidiabetic activity in overnight fasted leptin receptor deficient db/db C57BL/KSJ mouse assessed as reduction in postprandial blood glucose AUC at 10 mg/kg, po administered on day 10 post glucose challenge measured up to 120 mins by oral glucose tolerance test relative to control
|
Mus musculus
|
30.2
%
|
|
Journal : J Nat Prod
Title : Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.
Year : 2016
Volume : 79
Issue : 5
First Page : 1276
Last Page : 1284
Authors : Patel OP, Mishra A, Maurya R, Saini D, Pandey J, Taneja I, Raju KS, Kanojiya S, Shukla SK, Srivastava MN, Wahajuddin M, Tamrakar AK, Srivastava AK, Yadav PP.
Abstract : This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
|
Antidiabetic activity in overnight fasted leptin receptor deficient db/db C57BL/KSJ mouse assessed as reduction in postprandial blood glucose AUC at 10 mg/kg, po administered on day 15 post glucose challenge measured up to 120 mins by oral glucose tolerance test relative to control
|
Mus musculus
|
41.4
%
|
|
Journal : J Nat Prod
Title : Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.
Year : 2016
Volume : 79
Issue : 5
First Page : 1276
Last Page : 1284
Authors : Patel OP, Mishra A, Maurya R, Saini D, Pandey J, Taneja I, Raju KS, Kanojiya S, Shukla SK, Srivastava MN, Wahajuddin M, Tamrakar AK, Srivastava AK, Yadav PP.
Abstract : This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
|
Reversal of insulin resistance in leptin receptor deficient db/db C57BL/KSJ mouse assessed as decrease in serum insulin level administered for 15 consecutive days relative to control
|
Mus musculus
|
32.3
%
|
|
Journal : J Nat Prod
Title : Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.
Year : 2016
Volume : 79
Issue : 5
First Page : 1276
Last Page : 1284
Authors : Patel OP, Mishra A, Maurya R, Saini D, Pandey J, Taneja I, Raju KS, Kanojiya S, Shukla SK, Srivastava MN, Wahajuddin M, Tamrakar AK, Srivastava AK, Yadav PP.
Abstract : This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
|
Displacement of [3H]rosiglitazone from recombinant human C-terminal His-tagged MitoNEET cytosolic domain (32 to 108 residues) expressed in Escherichia coli BL21 by Cheng-Prusoff analysis
|
Homo sapiens
|
370.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of small molecules that bind to the mitochondrial protein mitoNEET.
Year : 2016
Volume : 26
Issue : 21
First Page : 5350
Last Page : 5353
Authors : Geldenhuys WJ, Yonutas HM, Morris DL, Sullivan PG, Darvesh AS, Leeper TC.
Abstract : MitoNEET (CISD1) is a 2Fe-2S iron-sulfur cluster protein belonging to the zinc-finger protein family. Recently mitoNEET has been shown to be a major role player in the mitochondrial function associated with metabolic type diseases such as obesity and cancers. The anti-diabetic drug pioglitazone and rosiglitazone were the first identified ligands to mitoNEET. Since little is known about structural requirements for ligand binding to mitoNEET, we screened a small set of compounds to gain insight into these requirements. We found that the thiazolidinedione (TZD) warhead as seen in rosiglitazone was not an absolutely necessity for binding to mitoNEET. These results will aid in the development of novel compounds that can be used to treat mitochondrial dysfunction seen in several diseases.
|
Transactivation at Gal4 fused PPARgamma LBD (unknown origin) expressed in African green monkey COS7 cells after 42 hrs by luciferase assay
|
Homo sapiens
|
320.0
nM
|
|
Journal : Eur J Med Chem
Title : New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile.
Year : 2016
Volume : 124
First Page : 138
Last Page : 152
Authors : Obermoser V, Urban ME, Murgueitio MS, Wolber G, Kintscher U, Gust R.
Abstract : In previous studies, the 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was identified as pharmacophoric core for PPARγ activation. In this structure-activity relationship study the C2-alkyl chain was elongated and the 2-COOH group was changed to a carbamide/carbonitrile or shifted to the 3- or 4-position. Furthermore, the benzo[d]imidazole was exchanged by 2,3-dihydrobenzo[d]thiazole or 1H-indole. C2-propyl derivatives showed the profile of partial agonists, while elongation of the C2-chain to that of an n-heptyl group or a 4-COOH shift changed the pharmacological profile to that of a potent full agonist. This finding can be explained by binding to the LBD in different ligand conformations. Two anchoring points (Tyr473 and Arg288) exist in the LBD, which have to be contacted to achieve receptor activation. In a crystal violet chemosensitivity assay using COS-7 cells and LNCaP cells expressing PPARγ only the carbamide derivatives influenced the cell growth, independently on the presence of the PPARγ. Therefore, receptor mediated cytotoxicity can be excluded.
|
Transactivation of GAL4-fused human PPARgamma ligand binding domain expressed in African green monkey COS7 cells after 42 hrs by dual luciferase reporter gene assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : Eur J Med Chem
Title : Evaluation of selected 3D virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR) γ partial agonists.
Year : 2016
Volume : 124
First Page : 49
Last Page : 62
Authors : Kaserer T, Obermoser V, Weninger A, Gust R, Schuster D.
Abstract : The peroxisome proliferator-activated receptor (PPAR) γ regulates the expression of genes involved in adipogenesis, lipid homeostasis, and glucose metabolism, making it a valuable drug target. However, full activation of the nuclear receptor is associated with unwanted side effects. Research therefore focuses on the discovery of novel partial agonists, which show a distinct protein-ligand interaction pattern compared to full agonists. Within this study, we employed pharmacophore- and shape-based virtual screening and docking independently and in parallel for the identification of novel PPARγ ligands. The ten top-ranked hits retrieved with every method were further investigated with external in silico bioactivity profiling tools. Subsequent biological testing not only confirmed the binding of nine out of the 29 selected test compounds, but enabled the direct comparison of the method performances in a prospective manner. Although all three methods successfully identified novel ligands, they varied in the numbers of active compounds ranked among the top-ten in the virtual hit list. In addition, these compounds were in most cases exclusively predicted as active by the method which initially identified them. This suggests, that the applied programs and methods are highly complementary and cover a distinct chemical space of PPARγ ligands. Further analyses revealed that eight out of the nine active molecules represent novel chemical scaffolds for PPARγ, which can serve as promising starting points for further chemical optimization. In addition, two novel compounds, identified with docking, proved to be partial agonists in the experimental testing.
|
Displacement of Fluoromone from GST-tagged recombinant human PPARgamma ligand binding domain at 10 uM by LanthaScreen TR-FRET assay relative to control
|
Homo sapiens
|
67.5
%
|
|
Journal : Eur J Med Chem
Title : Evaluation of selected 3D virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR) γ partial agonists.
Year : 2016
Volume : 124
First Page : 49
Last Page : 62
Authors : Kaserer T, Obermoser V, Weninger A, Gust R, Schuster D.
Abstract : The peroxisome proliferator-activated receptor (PPAR) γ regulates the expression of genes involved in adipogenesis, lipid homeostasis, and glucose metabolism, making it a valuable drug target. However, full activation of the nuclear receptor is associated with unwanted side effects. Research therefore focuses on the discovery of novel partial agonists, which show a distinct protein-ligand interaction pattern compared to full agonists. Within this study, we employed pharmacophore- and shape-based virtual screening and docking independently and in parallel for the identification of novel PPARγ ligands. The ten top-ranked hits retrieved with every method were further investigated with external in silico bioactivity profiling tools. Subsequent biological testing not only confirmed the binding of nine out of the 29 selected test compounds, but enabled the direct comparison of the method performances in a prospective manner. Although all three methods successfully identified novel ligands, they varied in the numbers of active compounds ranked among the top-ten in the virtual hit list. In addition, these compounds were in most cases exclusively predicted as active by the method which initially identified them. This suggests, that the applied programs and methods are highly complementary and cover a distinct chemical space of PPARγ ligands. Further analyses revealed that eight out of the nine active molecules represent novel chemical scaffolds for PPARγ, which can serve as promising starting points for further chemical optimization. In addition, two novel compounds, identified with docking, proved to be partial agonists in the experimental testing.
|
Transactivation of Gal4 fused human PPARgamma LBD expressed in African green monkey COS7 cells after 42 hrs by dual luciferase reporter gene assay
|
Homo sapiens
|
380.0
nM
|
|
Journal : Eur J Med Chem
Title : Importance of 5/6-aryl substitution on the pharmacological profile of 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid derived PPARγ agonists.
Year : 2017
Volume : 126
First Page : 590
Last Page : 603
Authors : Obermoser V, Mauersberger R, Schuster D, Czifersky M, Lipova M, Siegl M, Kintscher U, Gust R.
Abstract : In this structure-activity relationship study, the influence of aryl substituents at position 5 or 6 on the pharmacological profile of the partial PPARγ agonist 4'-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was investigated. This lead was previously identified as the essential part of telmisartan to induce PPARγ activation. Para-OCH3-phenyl substitution strongly increased potency and efficacy independent of the position. Both compounds represent full agonists because of strong hydrophobic contacts with the amino acid Phe363 in the ligand binding domain. Partial agonists with higher potency than telmisartan or the lead were obtained with OH or Cl substituents at the phenyl ring. Molecular modeling suggested additional hydrogen or halogen bonds with Phe360 located at helix 7. It is assumed that these interactions fix helix 7, thereby promoting a partial agonist conformation of the receptor. The theoretical considerations correlate very well with the results from the luciferase transactivation assay using hPPARγ-LBD as well as those from a time-resolved fluorescent resonance energy transfer (TR-FRET) assay in which the coactivator (TRAP220, PGC-1α) recruitment and corepressor (NCoR1) release pattern was investigated.
|
Inhibition of human BSEP expressed in fall armyworm sf9 cell plasma membrane vesicles assessed as reduction in vesicle-associated [3H]-taurocholate transport preincubated for 10 mins prior to ATP addition measured after 15 mins in presence of [3H]-taurocholate by topcount based membrane vesicle transport assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Toxicol Sci
Title : Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.
Year : 2010
Volume : 118
Issue : 2
First Page : 485
Last Page : 500
Authors : Morgan RE, Trauner M, van Staden CJ, Lee PH, Ramachandran B, Eschenberg M, Afshari CA, Qualls CW, Lightfoot-Dunn R, Hamadeh HK.
Abstract : The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.
|
Inhibition of recombinant human BSEP expressed in baculovirus infected sf9 cell plasma membrane vesicles assessed as reduction in ATP-dependent [3H]-taurocholate uptake in to vesicles preincubated for 10 mins followed by ATP addition measured after 10 to 15 mins by TopCount method
|
Homo sapiens
|
400.0
nM
|
|
Journal : Hepatology
Title : Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump.
Year : 2014
Volume : 60
Issue : 3
First Page : 1015
Last Page : 1022
Authors : Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y.
Abstract : Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.
|
Induction of mitochondrial dysfunction in Sprague-Dawley rat liver mitochondria assessed as inhibition of mitochondrial respiration per mg mitochondrial protein measured for 20 mins by A65N-1 oxygen probe based fluorescence assay
|
Rattus norvegicus
|
100.0
nM
|
|
Journal : Hepatology
Title : Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump.
Year : 2014
Volume : 60
Issue : 3
First Page : 1015
Last Page : 1022
Authors : Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y.
Abstract : Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.
|
Inhibition of human BSEP expressed in baculovirus transfected fall armyworm Sf21 cell membranes vesicles assessed as reduction in ATP-dependent [3H]-taurocholate transport into vesicles incubated for 5 mins by Topcount based rapid filtration method
|
Homo sapiens
|
262.1
nM
|
|
Journal : Drug Metab Dispos
Title : Mitigating the inhibition of human bile salt export pump by drugs: opportunities provided by physicochemical property modulation, in silico modeling, and structural modification.
Year : 2012
Volume : 40
Issue : 12
First Page : 2332
Last Page : 2341
Authors : Warner DJ, Chen H, Cantin LD, Kenna JG, Stahl S, Walker CL, Noeske T.
Abstract : The human bile salt export pump (BSEP) is a membrane protein expressed on the canalicular plasma membrane domain of hepatocytes, which mediates active transport of unconjugated and conjugated bile salts from liver cells into bile. BSEP activity therefore plays an important role in bile flow. In humans, genetically inherited defects in BSEP expression or activity cause cholestatic liver injury, and many drugs that cause cholestatic drug-induced liver injury (DILI) in humans have been shown to inhibit BSEP activity in vitro and in vivo. These findings suggest that inhibition of BSEP activity by drugs could be one of the mechanisms that initiate human DILI. To gain insight into the chemical features responsible for BSEP inhibition, we have used a recently described in vitro membrane vesicle BSEP inhibition assay to quantify transporter inhibition for a set of 624 compounds. The relationship between BSEP inhibition and molecular physicochemical properties was investigated, and our results show that lipophilicity and molecular size are significantly correlated with BSEP inhibition. This data set was further used to build predictive BSEP classification models through multiple quantitative structure-activity relationship modeling approaches. The highest level of predictive accuracy was provided by a support vector machine model (accuracy = 0.87, κ = 0.74). These analyses highlight the potential value that can be gained by combining computational methods with experimental efforts in early stages of drug discovery projects to minimize the propensity of drug candidates to inhibit BSEP.
|
Inhibition of human BSEP overexpressed in Sf9 cell membrane vesicles assessed as uptake of [3H]-taurocholate in presence of ATP measured after 15 to 20 mins by membrane vesicle transport assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Toxicol Sci
Title : A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development.
Year : 2013
Volume : 136
Issue : 1
First Page : 216
Last Page : 241
Authors : Morgan RE, van Staden CJ, Chen Y, Kalyanaraman N, Kalanzi J, Dunn RT, Afshari CA, Hamadeh HK.
Abstract : The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.
|
Agonist activity at PPARgamma in human HepG2 cells assessed as activation of PPRE incubated for 24 hrs by dual luciferase reporter gene assay
|
Homo sapiens
|
240.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, and evaluation of novel l-phenylglycine derivatives as potential PPARγ lead compounds.
Year : 2018
Volume : 26
Issue : 14
First Page : 4153
Last Page : 4167
Authors : Liu J, Su X, Li H, Fan L, Li Y, Tang X, Yan J, Chen X, Chen F, Liu J, Yang D.
Abstract : In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10 μg·mL-1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10 μg·mL-1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC50) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.
|
Transactivation of GAL4-DBD fused human PPARgamma ligand binding domain expressed in UAS-bla HEL 293H cells preincubated for 16 hrs followed by FRET substrate addition and measured after 2 hrs by TR-FRET assay
|
Homo sapiens
|
98.0
nM
|
|
Journal : Bioorg Med Chem
Title : PPARγ-sparing thiazolidinediones as insulin sensitizers. Design, synthesis and selection of compounds for clinical development.
Year : 2018
Volume : 26
Issue : 22
First Page : 5870
Last Page : 5884
Authors : Tanis SP, Colca JR, Parker TT, Artman GD, Larsen SD, McDonald WG, Gadwood RC, Kletzien RF, Zeller JB, Lee PH, Adams WJ.
|
Transactivation of human full length PPARgamma expressed in HEK293 cells after 18 hrs by luciferase reporter gene based luminescence assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Nat Prod
Title : Stereoselective Synthesis of the Isomers of Notoincisol A: Assigment of the Absolute Configuration of this Natural Product and Biological Evaluation.
Year : 2018
Volume : 81
Issue : 11
First Page : 2419
Last Page : 2428
Authors : Rycek L, Ticli V, Pyszkowski J, Latkolik S, Liu X, Atanasov AG, Steinacher T, Bauer R, Schuster D, Dirsch VM, Schnürch M, Ernst M, Mihovilovic MD.
Abstract : The total syntheses of all stereoisomers of notoincisol A, a recently isolated natural product with potential anti-inflammatory activity, are reported. The asymmetric synthesis was conducted employing a lipase-mediated kinetic resolution, which enables easy access to all required chiral building blocks with the aim of establishing the absolute configuration of the naturally occurring isomer. This was achieved by comparison of optical properties of the isolated compound with the synthetic derivatives obtained. Moreover, an assessment of the biological activity on PPARγ (peroxisome proliferator-activated receptor gamma) as a prominent receptor related to inflammation is reported. Only the natural isomer was found to activate the PPARγ receptor, and this phenomenon could be explained based on molecular docking studies. In addition, the pharmacological profiles of the isomers were determined using the GABAA (gamma-aminobutyric acid A) ion channel receptor as a representative target for allosteric modulation related to diverse CNS activities. These compounds were found to be weak allosteric modulators of the α1β3 and α1β2γ2 receptor subtypes.
|
IC50 for antiviral activity against SARS-CoV-2 in the Vero E6 cell line at 48 h by immunofluorescence-based assay (detecting the viral NP protein in the nucleus of the Vero E6 cells).
|
Chlorocebus sabaeus
|
676.08
nM
|
|
Journal : Nature
Title : A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
Year : 2020
Authors : David E Gordon, Gwendolyn M Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Kris M White, Matthew J O'Meara, Veronica V Rezelj, Jeffrey Z Guo, Danielle L Swaney, et al
Abstract : The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
|
Induction of adipogenesis in human bone marrow-derived mesenchymal stem cells assessed as increase in adiponectin production measured on day 5 in presence of IDX by ELISA
|
Homo sapiens
|
350.0
nM
|
|
Journal : J Nat Prod
Title : Adiponectin-Secretion-Promoting Phenylethylchromones from the Agarwood of Aquilaria malaccensis.
Year : 2019
Volume : 82
Issue : 2
First Page : 259
Last Page : 264
Authors : Ahn S, Ma CT, Choi JM, An S, Lee M, Le THV, Pyo JJ, Lee J, Choi MS, Kwon SW, Park JH, Noh M.
Abstract : The therapeutic potential of adiponectin regulation has received interest because of its association with diverse human disease conditions, such as diabetes, obesity, atherosclerosis, and cancer. Phenylethylchromone derivatives from Aquilaria malaccensis-derived agarwood promoted adiponectin secretion during adipogenesis in human bone marrow mesenchymal stem cells, and 5,6-dihydroxy-2-(2-phenylethyl)chromone (1) was identified as a new chromone derivative. A target identification study with the most potent adiponectin-secretion-promoting phenylethylchromones, 6-methoxy-2-(2-phenylethyl)chromone (3) and 7-methoxy-2-(2-phenylethyl)chromone (4), showed that they are PPARγ partial agonists. Therefore, the diverse therapeutic effects of agarwood are associated with a PPARγ-mediated adiponectin-secretion-promoting mechanism.
|
Binding affinity to PPARgamma (unknown origin) by TR-FRET assay
|
Homo sapiens
|
62.0
nM
|
|
Journal : J Nat Prod
Title : Adiponectin-Secretion-Promoting Phenylethylchromones from the Agarwood of Aquilaria malaccensis.
Year : 2019
Volume : 82
Issue : 2
First Page : 259
Last Page : 264
Authors : Ahn S, Ma CT, Choi JM, An S, Lee M, Le THV, Pyo JJ, Lee J, Choi MS, Kwon SW, Park JH, Noh M.
Abstract : The therapeutic potential of adiponectin regulation has received interest because of its association with diverse human disease conditions, such as diabetes, obesity, atherosclerosis, and cancer. Phenylethylchromone derivatives from Aquilaria malaccensis-derived agarwood promoted adiponectin secretion during adipogenesis in human bone marrow mesenchymal stem cells, and 5,6-dihydroxy-2-(2-phenylethyl)chromone (1) was identified as a new chromone derivative. A target identification study with the most potent adiponectin-secretion-promoting phenylethylchromones, 6-methoxy-2-(2-phenylethyl)chromone (3) and 7-methoxy-2-(2-phenylethyl)chromone (4), showed that they are PPARγ partial agonists. Therefore, the diverse therapeutic effects of agarwood are associated with a PPARγ-mediated adiponectin-secretion-promoting mechanism.
|
Agonist activity at PPARgamma (unknown origin)
|
Homo sapiens
|
970.0
nM
|
|
Journal : J Med Chem
Title : The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease.
Year : 2020
Volume : 63
Issue : 10
First Page : 5031
Last Page : 5073
Authors : Romero FA, Jones CT, Xu Y, Fenaux M, Halcomb RL.
Abstract : Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type 2 diabetes mellitus, and dyslipidemia has led to an emerging picture of NASH as the liver manifestation of metabolic syndrome. Although diet and exercise can dramatically improve NASH outcomes, significant lifestyle changes can be challenging to sustain. Pharmaceutical therapies could be an important addition to care, but currently none are approved for NASH. Here, we review the most promising targets for NASH treatment, along with the most advanced therapeutics in development. These include targets involved in metabolism (e.g., sugar, lipid, and cholesterol metabolism), inflammation, and fibrosis. Ultimately, combination therapies addressing multiple aspects of NASH pathogenesis are expected to provide benefit for patients.
|
Inhibition of PPARgamma (unknown origin) at 10 uM after 24 hrs relative to control
|
Homo sapiens
|
82.6
%
|
|
Journal : Eur J Med Chem
Title : Role of sulphur-heterocycles in medicinal chemistry: An update.
Year : 2019
Volume : 180
First Page : 486
Last Page : 508
Authors : Pathania S, Narang RK, Rawal RK.
Abstract : From many decades, S-heterocycles have maintained their status as an important part and core of FDA approved drugs and medicinally active compounds. With exhaustive exploration of nitrogen heterocycles in medicinal chemistry, researchers have shifted their interest towards other heterocycles, especially, S-heterocycles. Thus several attempts have been made to synthesize a variety of new sulphur containing compounds with high medicinal value and low toxicity profile, in comparison to previous N-heterocycles. Till today, S-heterocycle containing compounds have been largely reported as anticancer, antidiabetic, antimicrobial, antihypertension, antivral, antinflammatory etc. In this review, the authors have tried to provide a critical analysis of synthesis and medicinal attributes of sulphur containing heterocycles such as thiirane, thiophene, thiazole, thiopyran, thiazolidine etc reported within last five years to emphasize the significance and usefulness of these S-heterocycles in the drug discovery process.
|
Transactivation of chimeric Gal4 yeast DBD fused-PPARgamma LBD (unknown origin) expressed in HEK293T cells co-expressing PPRE after 18 hrs by luciferase reporter gene assay
|
Homo sapiens
|
350.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Year : 2019
Volume : 62
Issue : 4
First Page : 2008
Last Page : 2023
Authors : Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ.
Abstract : Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
|
Displacement of fluormone PanPPAR green tracer ligand from human 6His-tagged PPARgamma isoform 1 LBD (203 to 477 residues) expressed in Escherichia coli BL21(DE3) after 1 hr by TR-FRET assay
|
Homo sapiens
|
420.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Year : 2019
Volume : 62
Issue : 4
First Page : 2008
Last Page : 2023
Authors : Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ.
Abstract : Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
|
Activation of human 6His-tagged PPARgamma isoform 1 LBD (203 to 477 residues) expressed in Escherichia coli BL21(DE3) assessed as increase in FITC-TRAP220 peptide recruitment after 1 hr by FITC/TR-FRET assay
|
Homo sapiens
|
260.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Year : 2019
Volume : 62
Issue : 4
First Page : 2008
Last Page : 2023
Authors : Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ.
Abstract : Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
|
Binding affinity to human 6His-tagged PPARgamma LBD expressed in Escherichia coli BL21(DE3) using FITC-NTKNHPMLMNLLKDNPAQD peptide by isothermal titration calorimetry
|
Homo sapiens
|
871.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Year : 2019
Volume : 62
Issue : 4
First Page : 2008
Last Page : 2023
Authors : Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ.
Abstract : Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
|
Transactivation of full length human PPARgamma2 expressed in HEK293T cells co-expressing PPRE after 18 hrs by luciferase reporter gene assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : J Med Chem
Title : Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone.
Year : 2019
Volume : 62
Issue : 4
First Page : 2008
Last Page : 2023
Authors : Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ.
Abstract : Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallography and molecular docking analysis of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochemical phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry analysis coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.3
%
|
|
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
|
-0.14
%
|
|
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
|
-0.14
%
|
|
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.
|
Induction of adipogenesis in human MSC incubated for 5 days cotreated with IDX by ELISA
|
Homo sapiens
|
500.0
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.
|
Binding affinity to PPARgamma (unknown origin) by TR-FRET assay
|
Homo sapiens
|
340.0
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.
|
Inhibition of human BSEP expressed in HEK293 cell membrane vesicles assessed as reduction in 3H-TCA uptake incubated for 5 mins by radiodetection method
|
Homo sapiens
|
260.0
nM
|
|
Journal : J Med Chem
Title : Drug Induced Liver Injury (DILI). Mechanisms and Medicinal Chemistry Avoidance/Mitigation Strategies.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11397
Last Page : 11419
Authors : Norman BH
Abstract : Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI risk. Literature assessments and retrospective analyses using verified DILI-associated drugs from the Liver Tox Knowledge Base (LTKB) have been used to derive the predictive value of each end point, along with combination approaches of multiple methods. In vitro assays to assess inhibition of the bile salt export pump (BSEP), mitotoxicity, reactive metabolite (RM) formation, and hepatocyte cytolethality, along with physicochemical properties and clinical dose provide useful DILI predictivity. This Perspective also highlights some of the strategies used by medicinal chemists to reduce DILI risk during the optimization of drug candidates.
|
Binding affinity to PPAR-gamma (unknown origin) by TR-FRET assay
|
Homo sapiens
|
96.0
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.
|
Induction of adipogenesis in human BMMSC cotreated with IDX
|
Homo sapiens
|
340.0
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.
|
Inhibition of PTP1B in human HepG2 cells assessed as improvement in insulin-induced 2-NBDG uptake at 5 uM incubated for 24 hrs prior to compound washout followed by insulin stimulation for 20 mins and subsequent 2-NBDG addition measured after 60 mins by FACS analysis relative to control
|
Homo sapiens
|
33.8
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of geniposide derivatives as potent and selective PTPlB inhibitors.
Year : 2020
Volume : 205
First Page : 112508
Last Page : 112508
Authors : Lei S,Zhang D,Qi Y,Chowdhury SR,Sun R,Wang J,Du Y,Fu L,Jiang F
Abstract : Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTP1B inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC values of 0.35 and 0.41 μM, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity.
|
Inhibition of PTP1B in human HepG2 cells assessed as improvement in insulin-induced 2-NBDG uptake at 10 uM incubated for 24 hrs prior to compound washout followed by insulin stimulation for 20 mins and subsequent 2-NBDG addition measured after 60 mins by FACS analysis relative to control
|
Homo sapiens
|
46.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of geniposide derivatives as potent and selective PTPlB inhibitors.
Year : 2020
Volume : 205
First Page : 112508
Last Page : 112508
Authors : Lei S,Zhang D,Qi Y,Chowdhury SR,Sun R,Wang J,Du Y,Fu L,Jiang F
Abstract : Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTP1B inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC values of 0.35 and 0.41 μM, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity.
|
Inhibition of PTP1B in human HepG2 cells assessed as improvement in insulin-induced 2-NBDG uptake at 20 uM incubated for 24 hrs prior to compound washout followed by insulin stimulation for 20 mins and subsequent 2-NBDG addition measured after 60 mins by FACS analysis relative to control
|
Homo sapiens
|
63.5
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of geniposide derivatives as potent and selective PTPlB inhibitors.
Year : 2020
Volume : 205
First Page : 112508
Last Page : 112508
Authors : Lei S,Zhang D,Qi Y,Chowdhury SR,Sun R,Wang J,Du Y,Fu L,Jiang F
Abstract : Herein a series of Geniposide derivatives were designed, synthesized and evaluated as protein tyrosine phosphatase 1B (PTPlB) inhibitors. Most of these compounds exhibited potent in vitro PTP1B inhibitory activities, the representative 7a and 17f were found to be the most potent inhibitors against the enzyme with IC values of 0.35 and 0.41 μM, respectively. More importantly, they showcased 4 to10-fold selectivity over SHP2 and 3-fold over TCPTP. Further biological activity studies revealed that compounds 7a, 17b and 17f could effectively enhance insulin-stimulated glucose uptake with no significant cytotoxicity. Subsequent molecular docking and structural activity relationship analyses demonstrated that the glucose scaffold, benzylated glycosyl groups, and arylethenesulfonic acid ester significantly impact on the activity and selectivity.
