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Mairi Sime,
Amanda C Allan,
Paul Chapman,
Charlotte Fieldhouse,
Gerard M P Giblin,
Mark P Healy,
Millard H Lambert, Lisa M Leesnitzer,
Ann Lewis,
Raymond V Merrihew,
Richard A Rutter,
Rosemary Sasse,
Barry G Shearer,
Timothy M Wilson,
Robert X Xu,
David J Virley
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ABSTRACT: The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Bioorganic & medicinal chemistry letters 09/2011; 21(18):5568-72. · 2.65 Impact Factor
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Karen A Evans,
Barry G Shearer,
David D Wisnoski,
Dongchuan Shi,
Steven M Sparks,
Daniel D Sternbach,
Deborah A Winegar,
Andrew N Billin,
Christy Britt,
James M Way,
Andrea H Epperly, Lisa M Leesnitzer,
Raymond V Merrihew,
Robert X Xu,
Millard H Lambert,
Jian Jin
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ABSTRACT: A series of phenoxyacetic acids as subtype selective and potent hPPARδ partial agonists is described. Many analogues were readily accessible via a single solution-phase synthetic route which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of two potent exemplars which were further evaluated in vivo. Details of the SAR, optimization, and in vivo efficacy of this series are presented herein.
Bioorganic & medicinal chemistry letters 03/2011; 21(8):2345-50. · 2.65 Impact Factor
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Richard J Whitby,
Jozef Stec,
Raymond D Blind,
Sally Dixon, Lisa M Leesnitzer,
Lisa A Orband-Miller,
Shawn P Williams,
Timothy M Willson,
Robert Xu,
William J Zuercher,
Fang Cai,
Holly A Ingraham
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ABSTRACT: The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.
Journal of Medicinal Chemistry 03/2011; 54(7):2266-81. · 4.80 Impact Factor
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Sharon E Campbell,
Brittney Rudder,
Regenia B Phillips,
Sarah G Whaley,
Julie B Stimmel, Lisa M Leesnitzer,
Janet Lightner,
Sophie Dessus-Babus,
Michelle Duffourc,
William L Stone,
David G Menter,
Robert A Newman,
Peiying Yang,
Bharat B Aggarwal,
Koyamangalath Krishnan
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ABSTRACT: Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.
Free radical biology & medicine 02/2011; 50(10):1344-54. · 5.42 Impact Factor
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Cliona M Stapleton,
Douglas G Mashek,
Shuli Wang,
Cynthia A Nagle,
Gary W Cline,
Philippe Thuillier, Lisa M Leesnitzer,
Lei O Li,
Julie B Stimmel,
Gerald I Shulman,
Rosalind A Coleman
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ABSTRACT: Lysophosphatidic acid (LPA) is an agonist for peroxisome proliferator activated receptor-γ (PPARγ). Although glycerol-3-phosphate acyltransferase-1 (GPAT1) esterifies glycerol-3-phosphate to form LPA, an intermediate in the de novo synthesis of glycerolipids, it has been assumed that LPA synthesized by this route does not have a signaling role. The availability of Chinese Hamster Ovary (CHO) cells that stably overexpress GPAT1, allowed us to analyze PPARγ activation in the presence of LPA produced as an intracellular intermediate. LPA levels in CHO-GPAT1 cells were 6-fold higher than in wild-type CHO cells, and the mRNA abundance of CD36, a PPARγ target, was 2-fold higher. Transactivation assays showed that PPARγ activity was higher in the cells that overexpressed GPAT1. PPARγ activity was enhanced further in CHO-GPAT1 cells treated with the PPARγ ligand troglitazone. Extracellular LPA, phosphatidic acid (PA) or a membrane-permeable diacylglycerol had no effect, showing that PPARγ had been activated by LPA generated intracellularly. Transient transfection of a vector expressing 1-acylglycerol-3-phosphate acyltransferase-2, which converts endogenous LPA to PA, markedly reduced PPARγ activity, as did over-expressing diacylglycerol kinase, which converts DAG to PA, indicating that PA could be a potent inhibitor of PPARγ. These data suggest that LPA synthesized via the glycerol-3-phosphate pathway can activate PPARγ and that intermediates of de novo glycerolipid synthesis regulate gene expression.
PLoS ONE 01/2011; 6(4):e18932. · 4.09 Impact Factor
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Barry G Shearer,
Robert W Wiethe,
Adam Ashe,
Andrew N Billin,
James M Way,
Thomas B Stanley,
Craig D Wagner,
Robert X Xu, Lisa M Leesnitzer,
Raymond V Merrihew,
Todd W Shearer,
Michael R Jeune,
John C Ulrich,
Timothy M Willson
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ABSTRACT: 4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.
Journal of Medicinal Chemistry 02/2010; 53(4):1857-61. · 4.80 Impact Factor
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Sharon E Campbell,
Phillip R Musich,
Sarah G Whaley,
Julie B Stimmel, Lisa M Leesnitzer,
Sophie Dessus-Babus,
Michelle Duffourc,
William Stone,
Robert A Newman,
Peiying Yang,
Koyamangalath Krishnan
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ABSTRACT: Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer. Our previous studies in the colon have demonstrated that gamma-tocopherol treatment could upregulate the expression of peroxisome proliferator-activated preceptors (PPAR) gamma, a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation. In this study, we explored the possibility that gamma-tocopherol could induce growth arrest in PC-3 prostate cancer cells through the regulation of fatty acid metabolism. Growth arrest (40%) and PPAR gamma mRNA and protein upregulation was achieved with gamma-tocopherol within 6 h. gamma-Tocopherol-mediated growth arrest was demonstrated to be PPAR gamma dependent using the agonist GW9662 and a PPAR gamma dominant negative vector. gamma-tocopherol was shown not to be a direct PPAR gamma ligand, but rather 15-S-HETE (an endogenous PPAR gamma ligand) was upregulated by gamma-tocopherol treatment. 15-Lipoxygenase-2, a tumor suppressor and the enzyme that converts arachidonic acid to 15-S-HETE, was upregulated at 3 h following gamma-tocopherol treatment. Expression of proteins downstream of the PPAR gamma pathway were examined. Cyclin D1, cyclin D3, bcl-2, and NFkappa B proteins were found to be downregulated following gamma-tocopherol treatment. These data demonstrate that the growth arrest mediated by gamma-tocopherol follows a PPAR-gamma-dependent mechanism.
Nutrition and Cancer 01/2009; 61(5):649-62. · 2.78 Impact Factor
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Barry G Shearer,
Hari S Patel,
Andrew N Billin,
James M Way,
Deborah A Winegar,
Millard H Lambert,
Robert X Xu, Lisa M Leesnitzer,
Raymond V Merrihew,
Stephane Huet,
Timothy M Willson
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ABSTRACT: Anthranilic acid GW9371 was identified as a novel class of PPARdelta partial agonist through high-throughput screening. The design and synthesis of SAR analogues is described. GSK1115 and GSK7227 show potent partial agonism of the PPARdelta target genes CPT1a and PDK4 in skeletal muscle cells.
Bioorganic & medicinal chemistry letters 09/2008; 18(18):5018-22. · 2.65 Impact Factor
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Ryan P Trump,
Jeffrey E Cobb,
Barry G Shearer,
Millard H Lambert,
Robert T Nolte,
Timothy M Willson,
Richard G Buckholz,
Sumin M Zhao, Lisa M Leesnitzer,
Marie A Iannone,
Kenneth H Pearce,
Andrew N Billin,
William J Hoekstra
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ABSTRACT: PPARgamma-activating thiazolidinediones and carboxylic acids such as farglitazar exert their anti-diabetic effects in part in PPARgamma rich adipose. Both pro- and anti-adipogenic PPARgamma ligands promote glucose and lipid lowering in animal models of diabetes. Herein, we disclose representatives of an array of 160 farglitazar analogues with atypical inverse agonism of PPARgamma in mature adipocytes.
Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):3916-20. · 2.55 Impact Factor
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ABSTRACT: The ligand-binding domain (LBD) of apo-nuclear receptors in solution is thought to be a very dynamic structure with many possible conformations. Upon ligand binding, the structure is stabilized to a more rigid conformation. The dynamic stabilization assay is a LBD reassembly assay that takes advantage of the high specificity of the intramolecular interactions that comprise the ligand-bound LBD. Here, we demonstrate dynamic stabilization for the nuclear receptors peroxisome proliferator-activated receptor (PPAR)gamma and nerve growth factor inducible (NGFIB)beta and identify residues important for stabilization of the intramolecular interactions induced by PPARgamma ligands. Site-directed mutagenesis studies identified residues in helices 1 and 8 required for LBD reassembly. Further, disrupting the helix 1/8 interaction in the context of the holo-LBD alters the response of the receptor in a compound-specific manner, suggesting that residues far from the ligand-binding pocket can influence the stability of the ligand-bound receptor. Thus, these results support and extend models of the apo-LBD of PPARgamma as a dynamic structure.
Molecular Endocrinology 10/2003; 17(9):1704-14. · 4.54 Impact Factor
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ABSTRACT: Natural ligands for nuclear receptors are believed to activate gene transcription by causing dissociation of corepressors and promoting the association of coactivator proteins. Using multiple biophysical techniques, we find that peptides derived from one of the nuclear receptor interacting motifs of the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT) are able to bind the ligand binding domains (LBD) of all three PPAR (peroxisome proliferator activated receptor) subtypes. Using these peptides as tools, we find that ligands designed as selective agonists for PPAR gamma promote the association of coactivator peptides and dissociation of corepressor peptides as expected on PPAR gamma but surprisingly have varied effects on the binding of corepressor peptides to the other PPAR subtypes. In particular, some members of a class of L-tyrosine-based compounds designed as selective agonists for PPAR gamma reduce the affinity for corepressor peptides on PPAR gamma but increase the affinity for the same peptides on PPAR delta and in one case on PPAR alpha. We provide structural data that suggests that the molecular basis for these observations are variations in the ligand binding pockets of the three PPAR subtypes that are perturbed differentially by individual ligands and result in altered presentations of the overlapping coactivator/corepressor binding surfaces.
Biochemistry 09/2003; 42(31):9278-87. · 3.42 Impact Factor
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ABSTRACT: Diminished apoptosis, a critical event in tumorigenesis, is linked to down-regulated 15-lipoxygenase-1 (15-LOX-1) expression in colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which is the primary product of 15-LOX-1 metabolism of linoleic acid, restores apoptosis. Nonsteroidal antiinflammatory drugs (NSAIDs) transcriptionally up-regulate 15-LOX-1 expression to induce apoptosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for linoleic and arachidonic acid metabolites. PPAR-delta promotes colonic tumorigenesis. NSAIDs suppress PPAR-delta activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-delta was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-delta, decreases PPAR-delta activation, and down-regulates PPAR-delta expression in colorectal cancer cells; (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-delta and the resultant induction of apoptosis; and (iii) PPAR-delta is an important signaling receptor for 13-S-HODE-induced apoptosis. The in vivo relevance of these mechanistic findings was demonstrated in our tumorigenesis studies in nude mouse xenograft models. Our findings indicate that the down-regulation of PPAR-delta by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.
Proceedings of the National Academy of Sciences 09/2003; 100(17):9968-73. · 9.68 Impact Factor
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Andrew E Place,
Nanjoo Suh,
Charlotte R Williams,
Renee Risingsong,
Tadashi Honda,
Yukiko Honda,
Gordon W Gribble, Lisa M Leesnitzer,
Julie B Stimmel,
Timothy M Willson,
Evan Rosen,
Michael B Sporn
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ABSTRACT: 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a novel synthetic triterpenoid more potent than its parent compound, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), both in vitro and in vivo. CDDO-Im is highly active in suppressing cellular proliferation of human leukemia and breast cancer cell lines (IC(50), approximately 10-30 nM). In U937 leukemia cells, CDDO-Im also induces monocytic differentiation as measured by increased cell surface expression of CD11b and CD36. In each of these assays, CDDO-Im is several-fold more active than CDDO. Although CDDO and CDDO-Im both bind and transactivate peroxisome proliferator-activated receptor (PPAR) gamma, the irreversible PPARgamma antagonist GW9662 does not block the ability of either CDDO or CDDO-Im to induce differentiation; moreover, PPARgamma-null fibroblasts are still sensitive to the growth-suppressive effects of CDDO. Thus, CDDO-Im has significant actions independent of PPARgamma transactivation. In addition, the rexinoid LG100268 and the deltanoid ILX23-7553 (ILX7553) synergize with CDDO and CDDO-Im to induce differentiation. In vivo, CDDO-Im is a potent inhibitor of de novo inducible nitric oxide synthase expression in primary mouse macrophages. Moreover, CDDO-Im inhibits growth of B16 murine melanoma and L1210 murine leukemia cells in vivo. The potent effects of CDDO-Im, both in vitro and in vivo, suggest it should be considered for clinical use.
Clinical Cancer Research 08/2003; 9(7):2798-806. · 7.74 Impact Factor
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ABSTRACT: Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARalpha ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARalpha and PPARgamma. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.
Biochemical Journal 10/2002; 366(Pt 3):901-10. · 4.90 Impact Factor
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Lisa M Leesnitzer,
Derek J Parks,
Randy K Bledsoe,
Jeff E Cobb,
Jon L Collins,
Thomas G Consler,
Roderick G Davis,
Emily A Hull-Ryde,
James M Lenhard,
Lisa Patel,
Kelli D Plunket,
Jennifer L Shenk,
Julie B Stimmel,
Christina Therapontos,
Timothy M Willson,
Steven G Blanchard
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ABSTRACT: In the course of a high throughput screen to search for ligands of peroxisome proliferator activated receptor-gamma (PPARgamma), we identified GW9662 using a competition binding assay against the human ligand binding domain. GW9662 had nanomolar IC(50) versus PPARgamma and was 10- and 600-fold less potent in binding experiments using PPARalpha and PPARdelta, respectively. Pretreatment of all three PPARs with GW9662 resulted in the irreversible loss of ligand binding as assessed by scintillation proximity assay. Incubation of PPAR with GW9662 resulted in a change in the absorbance spectra of the receptors consistent with covalent modification. Mass spectrometric analysis of the PPARgamma ligand binding domain treated with GW9662 established Cys(285) as the site of covalent modification. This cysteine is conserved among all three PPARs. In cell-based reporter assays, GW9662 was a potent and selective antagonist of full-length PPARgamma. The functional activity of GW9662 as an antagonist of PPARgamma was confirmed in an assay of adipocyte differentiation. GW9662 showed essentially no effect on transcription when tested using both full-length PPARdelta and PPARalpha. Time-resolved fluorescence assays of ligand-modulated receptor heterodimerization, coactivator binding, and corepressor binding were consistent with the effects observed in the reporter gene assays. Control activators increased PPAR:RXR heterodimer formation and coactivator binding to both PPARgamma and PPARdelta. Corepressor binding was decreased. In the case of PPARalpha, GW9662 treatment did not significantly increase heterodimerization and coactivator binding or decrease corepressor binding. The experimental data indicate that GW9662 modification of each of the three PPARs results in different functional consequences. The selective and irreversible nature of GW9662 treatment, and the observation that activity is maintained in cell culture experiments, suggests that this compound may be a useful tool for elucidation of the role of PPARgamma in biological processes.
Biochemistry 06/2002; 41(21):6640-50. · 3.42 Impact Factor
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Brad R. Henke,
Steven G. Blanchard,
Marcus F. Brackeen,
Kathleen K. Brown,
Jeff E. Cobb,
Jon L. Collins,
W. Wallace Harrington, Jr,
Mir A. Hashim,
Emily A. Hull-Ryde,
Istvan Kaldor, [......],
James M. Lenhard,
Lisa A. Orband-Miller,
John F. Miller,
Robert A. Mook, Jr,
Stewart A. Noble,
William Oliver, Jr,
Derek J. Parks,
Kelli D. Plunket,
Jerzy R. Szewczyk,
Timothy M. Willson
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ABSTRACT: We have identified a novel series of antidiabetic N-(2-benzoylphenyl)-l-tyrosine derivatives which are potent, selective PPARγ agonists. Through the use of in vitro PPARγ binding and functional assays (2S)-3-(4-(benzyloxy)phenyl)-2-((1-methyl-3-oxo-3-phenylpropenyl)amino)propionic acid (2) was identified as a structurally novel PPARγ 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 PPARγ, affording a series of potent and selective PPARγ 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-benzoylphenyl)amino)propanoic acid (19), and (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]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 PPARγ agonists relative to troglitazone may translate into superior clinical efficacy for the treatment of type 2 diabetes.
11/1998;
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Jon L. Collins,
Steven G. Blanchard,
G. Evan Boswell,
Paul S. Charifson,
Jeff E. Cobb,
Brad R. Henke,
Emily A. Hull-Ryde,
Wieslaw M. Kazmierski,
Debra H. Lake, Lisa M. Leesnitzer,
Jürgen Lehmann,
James M. Lenhard,
Lisa A. Orband-Miller,
Yolanda Gray-Nunez,
Derek J. Parks,
Kelli D. Plunkett,
Wei-Qin Tong
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ABSTRACT: We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic acid (2) (PPARγ pKi = 8.94, PPARγ pEC50 = 9.47) as a potent and selective PPARγ agonist. We now report the expanded structure−activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPARγ agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (16) (PPARγ pKi = 8.85, PPARγ pEC50 = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}phenyl)propionic acid (24) (PPARγ pKi = 8.66, PPARγ pEC50 = 8.89) provided two potent and selective PPARγ agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPARγ ligands (PPARγ pKi's 6.98−8.03). The combined structure−activity data derived from the two strategies provide valuable insight on the requirements for PPARγ binding, functional activity, selectivity, and aqueous solubility.
Journal of Medicinal Chemistry 11/1998; 41(25). · 5.25 Impact Factor
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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 (PPARγ) are reported. These new analogs are selective for PPARγ vs the other PPAR subtypes, and the most potent compounds in this series are comparable to in vitro potencies at PPARγ reported for the thiazolidinedione-based antidiabetic drugs currently in clinical use.The synthesis and structure-activity relationships of a novel series of indole 5-carboxylic acids that bind and activate peroxisome proliferator-activated receptor gamma (PPARγ) are reported. These compounds are selective for PPARγ vs the other PPAR subtypes, and the most potent compounds have in vitro potencies at PPARγ comparable to those reported for the thiazolidinedione-based antidiabetic drugs currently in clinical use.
Bioorganic & Medicinal Chemistry Letters.
