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Changyou Zhou,
Cheng Tang,
Eric Chang,
Min Ge,
Songnian Lin,
Eric Cline,
Carina P Tan,
Yue Feng,
Yun-Ping Zhou,
George J Eiermann, [......],
Peter Meinke, Ralph Mosley,
Taro E Akiyama,
Monica Einstein,
Sanjeev Kumar,
Joel Berger,
Andrew D Howard,
Nancy Thornberry,
Sander G Mills,
Lihu Yang
[show abstract]
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ABSTRACT: Systematic structure-activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
Bioorganic & medicinal chemistry letters 02/2010; 20(3):1298-301. · 2.65 Impact Factor
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Carina P Tan,
Yue Feng,
Yun-Ping Zhou,
George J Eiermann,
Aleksandr Petrov,
Changyou Zhou,
Songnian Lin,
Gino Salituro,
Peter Meinke, Ralph Mosley,
Taro E Akiyama,
Monica Einstein,
Sanjeev Kumar,
Joel P Berger,
Sander G Mills,
Nancy A Thornberry,
Lihu Yang,
Andrew D Howard
[show abstract]
[hide abstract]
ABSTRACT: Acute activation of G protein-coupled receptor 40 (GPR40) by free fatty acids (FFAs) or synthetic GPR40 agonists enhances insulin secretion. However, it is still a matter of debate whether activation of GPR40 would be beneficial for the treatment of type 2 diabetes, since chronic exposure to FFAs impairs islet function. We sought to evaluate the specific role of GPR40 in islets and its potential as a therapeutic target using compounds that specifically activate GPR40.
We developed a series of GPR40-selective small-molecule agonists and studied their acute and chronic effects on glucose-dependent insulin secretion (GDIS) in isolated islets, as well as effects on blood glucose levels during intraperitoneal glucose tolerance tests in wild-type and GPR40 knockout mice (GPR40(-/-)).
Small-molecule GPR40 agonists significantly enhanced GDIS in isolated islets and improved glucose tolerance in wild-type mice but not in GPR40(-/-) mice. While a 72-h exposure to FFAs in tissue culture significantly impaired GDIS in islets from both wild-type and GPR40(-/-) mice, similar exposure to the GPR40 agonist did not impair GDIS in islets from wild-type mice. Furthermore, the GPR40 agonist enhanced insulin secretion in perfused pancreata from neonatal streptozotocin-induced diabetic rats and improved glucose levels in mice with high-fat diet-induced obesity acutely and chronically.
GPR40 does not mediate the chronic toxic effects of FFAs on islet function. Pharmacological activation of GPR40 may potentiate GDIS in humans and be beneficial for overall glucose control in patients with type 2 diabetes.
Diabetes 06/2008; 57(8):2211-9. · 8.29 Impact Factor
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Qiaolin Deng,
Joseph A Clemas,
Gary Chrebet,
Paul Fischer,
Jeffrey J Hale,
Zhen Li,
Sander G Mills,
James Bergstrom,
Suzanne Mandala, Ralph Mosley,
Stephen A Parent
[show abstract]
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ABSTRACT: Sphingosine-1-phosphate (S1P) receptor agonists are novel immunosuppressive agents. The selectivity of S1P1 against S1P3 is strongly correlated with lymphocyte sequestration and minimum acute toxicity and bradycardia. This study describes molecular modeling, site-directed mutagenesis, and affinity studies exploring the molecular basis for selectivity between S1P1 and S1P3 receptors. Computational models of human S1P1 and S1P3 receptors bound with two nonselective agonists or two S1P1-selective agonists were developed based on the X-ray crystal structure of bovine rhodopsin. The models predict that S1P1 Leu276 and S1P3 Phe263 contribute to the S1P1/S1P3 selectivity of the two S1P1-selective agonists. These residues were subjected to site-directed mutagenesis. The wild-type and mutant S1P receptors were expressed in Chinese hamster ovary cells and examined for their abilities to bind to and be activated by agonists in vitro. The results indicate that the mutations have minimal effects on the activities of the two nonselective agonists, although they have dramatic effects on the S1P1-selective agonists. These studies provide a fundamental understanding of how these two receptor-selective agonists bind to the S1P1 and S1P3 receptors, which should aid development of more selective S1P1 receptor agonists with immunosuppressive properties and improved safety profiles.
Molecular Pharmacology 04/2007; 71(3):724-35. · 4.88 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: A series of 6H-benzo[c]chromen-6-one and 6H-benzo[c]chromene derivatives were prepared, and the affinity and selectivity for ERalpha and ERbeta was measured. Many of the analogs were found to be potent and selective ERbeta agonists. Bis hydroxyl at positions 3 and 8 is essential for activity in a HTRF coactivator recruitment assay. Additional modifications at both phenyl rings led to compounds with ERbeta<10nM potency and >100-fold selectivity over ERalpha.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(6):1468-72. · 2.55 Impact Factor
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Kun Liu,
Regina M Black,
John J Acton, Ralph Mosley,
Sheryl Debenham,
Ramon Abola,
Meng Yang,
Richard Tschirret-Guth,
Lawrence Colwell,
Cherrie Liu,
Margaret Wu,
Chuanlin F Wang,
Karen L MacNaul,
Margaret E McCann,
David E Moller,
Joel P Berger,
Peter T Meinke,
A Brian Jones,
Harold B Wood
[show abstract]
[hide abstract]
ABSTRACT: A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.
Bioorganic & Medicinal Chemistry Letters 06/2005; 15(10):2437-40. · 2.55 Impact Factor
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Qiaolin Deng,
Zhijian Lu,
Joann Bohn,
Kenneth P Ellsworth,
Robert W Myers,
Wayne M Geissler,
Georgianna Harris,
Christopher A Willoughby,
Kevin Chapman,
Brian McKeever, Ralph Mosley
[show abstract]
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ABSTRACT: Molecular modeling has been used to assist in the development of a novel series of potent glycogen phosphorylase inhibitors based on a phenyl diacid lead, compound 1. In the absence of suitable competitive binding assays, compound 1 was predicted to bind at the AMP allosteric site based on superposition onto known inhibitors which bind at different sites in the enzyme and analyses of the surrounding protein environment associated with these distinct sites. Possible docking modes of compound 1 at the AMP allosteric site were further explored using the crystal structure of rabbit muscle glycogen phosphorylase complexed with a Bayer diacid compound W1807 (PDB entry 3AMV). Compound 1 was predicted to interact with positively charged arginines at the AMP allosteric site in the docking model. Characterization of the binding pocket by a grid-based surface calculation of the docking model revealed a large unfilled hydrophobic region near the central phenyl ring, suggesting that compounds with larger hydrophobic groups in this region would improve binding. A series of naphthyl diacid compounds were designed and synthesized to access this hydrophobic cleft, and showed significantly improved potency.
Journal of Molecular Graphics and Modelling 05/2005; 23(5):457-64. · 2.18 Impact Factor
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Joel P Berger,
Ann E Petro,
Karen L Macnaul,
Linda J Kelly,
Bei B Zhang,
Karen Richards,
Alex Elbrecht,
Bruce A Johnson,
Gaochao Zhou,
Thomas W Doebber,
Chhabi Biswas,
Mona Parikh,
Neelam Sharma,
Michael R Tanen,
G Marie Thompson,
John Ventre,
Alan D Adams, Ralph Mosley,
Richard S Surwit,
David E Moller
[show abstract]
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ABSTRACT: Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.
Molecular Endocrinology 05/2003; 17(4):662-76. · 4.54 Impact Factor
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Conrad Santini,
Gregory D Berger,
Wei Han, Ralph Mosley,
Karen MacNaul,
Joel Berger,
Thomas Doebber,
Margaret Wu,
David E Moller,
Richard L Tolman,
Soumya P Sahoo
[show abstract]
[hide abstract]
ABSTRACT: Beginning with the weakly active lead structure 1, a new series of hPPAR agonists was developed. In vivo glucose and triglyceride lowering activity was obtained by homologation and oxamination to 3, then conversion to substituted benzisoxazoles 4 and 5. Further manipulation afforded benzofurans 6 and 7. Compound 7 was of comparable potency as a glucose and triglyceride lowering agent in insulin resistant rodents to BRL 49653.
Bioorganic & Medicinal Chemistry Letters 05/2003; 13(7):1277-80. · 2.55 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Nuclear receptor activation is dependent on recruitment of coactivators, including CREB-binding protein (CBP/p300) and steroid
receptor coactivator-1 (SRC-1). A three-dimensional NMR approach was used to probe the coactivator binding interface in the
peroxisome proliferator-activated receptor γ (PPARγ) ligand binding domain (LBD). In the presence of a CBP peptide, peaks
corresponding to 20 residues in helices 3, 4, 5, and 12 of the LBD were attenuated. Alanine mutants revealed that K301A, V315A,
Y320A, L468A, and E471A were required for binding of both CBP and SRC-1 and for cell-based transcription. Several additional
amino acids in helix 4 of the PPARγLBD were defective with respect to CBP recruitment, but retained relatively normal SRC-1
recruitment. Thus these amino acid residues may be important determinants of specificity for nuclear receptor LBD interactions
with discrete coactivator molecules.
Journal of Biological Chemistry 02/2000; 275(6):3733-3736. · 4.77 Impact Factor
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Joel Berger,
Mark D. Leibowitz,
Thomas W. Doebber,
Alex Elbrecht,
Bei Zhang,
Gaochou Zhou,
Chhabi Biswas,
Catherine A. Cullinan,
Nancy S. Hayes,
Ying Li, [......],
John Ventre,
Margaret S. Wu,
Gregory D. Berger, Ralph Mosley,
Robert Marquis,
Conrad Santini,
Soumya P. Sahoo,
Richard L. Tolman,
Roy G. Smith,
David E. Moller
[show abstract]
[hide abstract]
ABSTRACT: The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPARα,
PPARδ, and PPARγ. PPARγ has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione
drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPARγ and PPARδ that were identified
by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they
bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both
PPARγ and PPARδ directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner.
Only the PPARγ agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabeticdb/db mice all PPARγ agonists were orally active insulin-sensitizing agents producing reductions of elevated plasma glucose and
triglyceride concentrations. In contrast, selectivein vivo activation of PPARδ did not significantly affect these parameters. In vivo PPARα activation with WY-14653 resulted in reductions in elevated triglyceride levels with minimal effect on hyperglycemia.
We conclude that: 1) synthetic non-thiazolidinediones can serve as ligands of PPARγ and PPARδ; 2) ligand-dependent activation
of PPARδ involves an apparent conformational change and association of the receptor ligand binding domain with CREB-binding
protein; 3) PPARγ activation (but not PPARδ or PPARα activation) is sufficient to potentiate preadipocyte differentiation;
4) non-thiazolidinedione PPARγ agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5) although PPARα activation is sufficient to affect triglyceride metabolism, PPARδ activation does not appear to modulate
glucose or triglyceride levels.
Journal of Biological Chemistry 03/1999; 274(10):6718-6725. · 4.77 Impact Factor
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Kun Liu,
Regina M. Black,
John J. Acton III, Ralph Mosley,
Sheryl Debenham,
Ramon Abola,
Meng Yang,
Richard Tschirret-Guth,
Lawrence Colwell,
Cherrie Liu,
Margaret Wu,
Chuanlin F. Wang,
Karen L. MacNaul,
Margaret E. McCann,
David E. Moller,
Joel P. Berger,
Peter T. Meinke,
A. Brian Jones,
Harold B. Wood
[show abstract]
[hide abstract]
ABSTRACT: A series of metabolically robust N-benzyl-indole selective PPARγ modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARγMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARγ full agonists.Graphical abstract
Bioorganic & Medicinal Chemistry Letters. 15(10):2437-2440.
