Patricia Pelton

Publications (7)23.97 Total impact

• Article: Design, synthesis, and biological evaluation of (2R,alphaS)-3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(trifluoromethoxy)-phenyl]-alpha-(trifluoromethyl)-1(2H)-quinolineethanol as potent and orally active cholesteryl ester transfer protein inhibitor.

  Gee-Hong Kuo, Thomas Rano, Patricia Pelton, Keith T Demarest, Alan C Gibbs, William V Murray, Bruce P Damiano, Margery A Connelly
  [show abstract] [hide abstract]
  ABSTRACT: With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
  Journal of Medicinal Chemistry 03/2009; 52(6):1768-72. · 4.80 Impact Factor
• Article: Discovery and SAR of para-alkylthiophenoxyacetic acids as potent and selective PPARdelta agonists.

  Rui Zhang, Alan Deangelis, Aihua Wang, Ellen Sieber-McMaster, Xun Li, Ronald Russell, Patricia Pelton, Jun Xu, Peifang Zhu, Lubing Zhou, Keith Demarest, William V Murray, Gee-Hong Kuo
  [show abstract] [hide abstract]
  ABSTRACT: Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.
  Bioorganic & medicinal chemistry letters 02/2009; 19(4):1101-4. · 2.65 Impact Factor
• Article: Improvement of dyslipidemia, insulin sensitivity, and energy balance by a peroxisome proliferator-activated receptor alpha agonist.

  Xiaoli Chen, Jay Matthews, Lubing Zhou, Patricia Pelton, Yin Liang, Jun Xu, Maria Yang, Ellen Cryan, Philip Rybczynski, Keith Demarest
  [show abstract] [hide abstract]
  ABSTRACT: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.
  Metabolism: clinical and experimental 12/2008; 57(11):1516-25. · 2.59 Impact Factor
• Article: Synthesis and structure-activity relationships of thiadiazole-derivatives as potent and orally active peroxisome proliferator-activated receptors alpha/delta dual agonists.

  Lan Shen, Yan Zhang, Aihua Wang, Ellen Sieber-McMaster, Xiaoli Chen, Patricia Pelton, June Z Xu, Maria Yang, Peifang Zhu, Lubing Zhou, Michael Reuman, Zhiyong Hu, Ronald Russell, Alan C Gibbs, Hamish Ross, Keith Demarest, William V Murray, Gee-Hong Kuo
  [show abstract] [hide abstract]
  ABSTRACT: Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.
  Bioorganic & medicinal chemistry 04/2008; 16(6):3321-41. · 2.82 Impact Factor
• Article: Synthesis and identification of [1,2,4]thiadiazole derivatives as a new series of potent and orally active dual agonists of peroxisome proliferator-activated receptors alpha and delta.

  Lan Shen, Yan Zhang, Aihua Wang, Ellen Sieber-McMaster, Xiaoli Chen, Patricia Pelton, Jun Z Xu, Maria Yang, Peifang Zhu, Lubing Zhou, Michael Reuman, Zhiyong Hu, Ronald Russell, Alan C Gibbs, Hamish Ross, Keith Demarest, William V Murray, Gee-Hong Kuo
  [show abstract] [hide abstract]
  ABSTRACT: Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.
  Journal of Medicinal Chemistry 09/2007; 50(16):3954-63. · 5.25 Impact Factor
• Article: Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARdelta agonists.

  Rui Zhang, Aihua Wang, Alan DeAngelis, Patricia Pelton, Jun Xu, Peifang Zhu, Lubing Zhou, Keith Demarest, William V Murray, Gee-Hong Kuo
  [show abstract] [hide abstract]
  ABSTRACT: A novel series of potent and selective PPARdelta agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described.
  Bioorganic & Medicinal Chemistry Letters 08/2007; 17(14):3855-9. · 2.55 Impact Factor
• Article: GW-501516 GlaxoSmithKline/Ligand.

  Patricia Pelton
  [show abstract] [hide abstract]
  ABSTRACT: GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia. Phase II clinical trials of this compound are ongoing.
  Current opinion in investigational drugs (London, England: 2000) 05/2006; 7(4):360-70. · 3.31 Impact Factor