Thomas Harrity

Publications (15)51.75 Total impact

• Article: Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11β-hydroxydehydrogenase 1 (11β-HSD1).

  Shung C Wu, David Yoon, Janice Chin, Katy van Kirk, Ramakrishna Seethala, Rajasree Golla, Bin He, Thomas Harrity, Lori K Kunselman, Nathan N Morgan, [......], Paul E Morin, John G Everlof, Yi-Xin Li, Cheryl A Ferraro, Kasia Kieltyka, Wilson Shou, Marianne B Vath, Tatyana A Zvyaga, David A Gordon, Jeffrey A Robl
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  ABSTRACT: Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11β-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
  Bioorganic & medicinal chemistry letters 11/2011; 21(22):6693-8. · 2.65 Impact Factor
• Article: Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors.

  Wei Meng, Robert P Brigance, Hannguang J Chao, Aberra Fura, Thomas Harrity, Jovita Marcinkeviciene, Stephen P O'Connor, James K Tamura, Dianlin Xie, Yaqun Zhang, Herbert E Klei, Kevin Kish, Carolyn A Weigelt, Huji Turdi, Aiying Wang, Robert Zahler, Mark S Kirby, Lawrence G Hamann
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  ABSTRACT: Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
  Journal of Medicinal Chemistry 08/2010; 53(15):5620-8. · 4.80 Impact Factor
• Article: Synthesis and SAR of azolopyrimidines as potent and selective dipeptidyl peptidase-4 (DPP4) inhibitors for type 2 diabetes.

  Robert P Brigance, Wei Meng, Aberra Fura, Thomas Harrity, Aiying Wang, Robert Zahler, Mark S Kirby, Lawrence G Hamann
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  ABSTRACT: Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
  Bioorganic & medicinal chemistry letters 08/2010; 20(15):4395-8. · 2.65 Impact Factor
• Article: Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).

  Jun Li, Lawrence J Kennedy, Yan Shi, Shiwei Tao, Xiang-Yang Ye, Stephanie Y Chen, Ying Wang, Andrés S Hernández, Wei Wang, Pratik V Devasthale, [......], Yi-Xin Li, Jodi K Muckelbauer, Chiehying Chang, Yongmi An, Stanley R Krystek, Michael A Blanar, Robert Zahler, Ranjan Mukherjee, Peter T W Cheng, Joseph A Tino
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  ABSTRACT: An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
  Journal of Medicinal Chemistry 03/2010; 53(7):2854-64. · 4.80 Impact Factor
• Article: Design, synthesis and structure-activity relationships of azole acids as novel, potent dual PPAR alpha/gamma agonists.

  Hao Zhang, Denis E Ryono, Pratik Devasthale, Wei Wang, Kevin O'Malley, Dennis Farrelly, Liqun Gu, Thomas Harrity, Michael Cap, Cuixia Chu, [......], Lisa Zhang, Pathanjali Kadiyala, Carrie Xu, Arthur M Doweyko, Aneka Bell, Chiehying Chang, Jodi Muckelbauer, Robert Zahler, Narayanan Hariharan, Peter T W Cheng
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  ABSTRACT: The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.
  Bioorganic & medicinal chemistry letters 02/2009; 19(5):1451-6. · 2.65 Impact Factor
• Article: (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential.

  Saleem Ahmad, Cort S Madsen, Philip D Stein, Evan Janovitz, Christine Huang, Khehyong Ngu, Sharon Bisaha, Lawrence J Kennedy, Bang-Chi Chen, Rulin Zhao, [......], Van Nguyen-Tran, Carolyn A Cuff, Thomas Harrity, Celia J Darienzo, Tong Li, Richard A Reeves, Michael A Blanar, Joel C Barrish, Robert Zahler, Jeffrey A Robl
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  ABSTRACT: 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
  Journal of Medicinal Chemistry 06/2008; 51(9):2722-33. · 5.25 Impact Factor
• Article: Discovery of azetidinone acids as conformationally-constrained dual PPARalpha/gamma agonists.

  Wei Wang, Pratik Devasthale, Dennis Farrelly, Liqun Gu, Thomas Harrity, Michael Cap, Cuixia Chu, Lori Kunselman, Nathan Morgan, Randy Ponticiello, [......], Vinayak Hosagrahara, Lisa Zhang, Pathanjali Kadiyala, Chiehying Chang, Jodi Muckelbauer, Arthur M Doweyko, Robert Zahler, Denis Ryono, Narayanan Hariharan, Peter T W Cheng
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  ABSTRACT: A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
  Bioorganic & medicinal chemistry letters 04/2008; 18(6):1939-44. · 2.65 Impact Factor
• Article: The Guinea pig as a preclinical model for demonstrating the efficacy and safety of statins.

  Cort S Madsen, Evan Janovitz, Rongan Zhang, Van Nguyen-Tran, Carol S Ryan, Xiaohong Yin, Hossain Monshizadegan, Ming Chang, Celia D'Arienzo, Susan Scheer, [......], Andrew Peters, Thomas Harrity, Atsu Apedo, Christine Huang, Carolyn A Cuff, Mark C Kowala, Michael A Blanar, Chong-Qing Sun, Jeffrey A Robl, Philip D Stein
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  ABSTRACT: Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced myotoxicity at doses near the ED(50) for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model, which used statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.
  Journal of Pharmacology and Experimental Therapeutics 03/2008; 324(2):576-86. · 3.83 Impact Factor
• Article: Potent and selective biphenyl azole inhibitors of adipocyte fatty acid binding protein (aFABP).

  Richard Sulsky, David R Magnin, Yanting Huang, Ligaya Simpkins, Prakash Taunk, Manorama Patel, Yeheng Zhu, Terry R Stouch, Donna Bassolino-Klimas, Rex Parker, Thomas Harrity, Robert Stoffel, David S Taylor, Thomas B Lavoie, Kevin Kish, Bruce L Jacobson, Steven Sheriff, Leonard P Adam, William R Ewing, Jeffrey A Robl
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  ABSTRACT: Herein we report the first disclosure of biphenyl azoles that are nanomolar binders of adipocyte fatty acid binding protein (aFABP or aP2) with up to thousand-fold selectivity against muscle fatty acid binding protein and epidermal fatty acid binding protein. In addition a new radio-ligand to determine binding against the three fatty acid binding proteins was also synthesized.
  Bioorganic & Medicinal Chemistry Letters 07/2007; 17(12):3511-5. · 2.55 Impact Factor
• Article: 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors.

  James J Li, Haixia Wang, Joseph A Tino, Jeffrey A Robl, Timothy F Herpin, R Michael Lawrence, Scott Biller, Haris Jamil, Randy Ponticiello, Luping Chen, [......], Neil Flynn, Dong Cheng, Rulin Zhao, Bangchi Chen, Dora Schnur, Mary T Obermeier, Vito Sasseville, Ramesh Padmanabha, Kristen Pike, Thomas Harrity
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  ABSTRACT: A novel series of 2-hydroxy-N-arylbenzenesulfonamides were identified to be ATP-citrate lyase (ACL) inhibitors with compound 9 displaying potent in vitro activity (IC(50)=0.13 microM). Chronic oral dosing of compound 9 in high-fat fed mice lowered plasma cholesterol, triglyceride, and glucose, as well as inhibited weight gain.
  Bioorganic & Medicinal Chemistry Letters 07/2007; 17(11):3208-11. · 2.55 Impact Factor
• Article: The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice.

  Effie Tozzo, Randolph Ponticiello, JoAnn Swartz, Dennis Farrelly, Rachel Zebo, Gustav Welzel, Donald Egan, Lori Kunselman, Andrew Peters, Liqun Gu, [......], Sean Chen, Pratik Devasthale, Evan Janovitz, Ada Staal, Thomas Harrity, Rene Belder, Peter T Cheng, Jean Whaley, Simeon Taylor, Narayanan Hariharan
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  ABSTRACT: There are two major defects in type 2 diabetes: 1) insulin resistance and 2) insulin deficiency due to loss of beta-cell function. Here we demonstrated that treatment with muraglitazar (a dual peroxisome proliferator-activated receptor alpha/gamma activator), when initiated before or after the onset of diabetes in mice, is effective against both defects. In study 1, prediabetic db/db mice were treated for 12 weeks. The control mice developed diabetes, as evidenced by hyperglycemia, hyperinsulinemia, reduced insulin levels in the pancreas, blunted insulin response to glucose, and impaired glucose tolerance. The muraglitazar-treated mice had normal plasma glucose, and insulin levels, equivalent or higher pancreatic insulin content than normal mice, showed a robust insulin response to glucose and exhibited greater glucose tolerance. In study 2, diabetic db/db mice were treated for 4 weeks. The control mice displayed increased glucose levels, severe loss of islets, and their isolated islets secreted reduced amounts of insulin in response to glucose and exendin-4 compared with baseline. In muraglitazar-treated mice, glucose levels were reduced to normal. These mice showed reduced loss of islets, and their isolated islets secreted insulin at levels comparable to baseline. Thus, muraglitazar treatment decreased both insulin resistance and preserved beta-cell function. As a result, muraglitazar treatment, when initiated before the onset of diabetes, prevented development of diabetes and, when initiated after the onset of diabetes, prevented worsening of diabetes in db/db mice.
  Journal of Pharmacology and Experimental Therapeutics 05/2007; 321(1):107-15. · 3.83 Impact Factor
• Article: Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor activator, improves diabetes and other metabolic abnormalities and preserves beta-cell function in db/db mice.

  Thomas Harrity, Dennis Farrelly, Aaron Tieman, Cuixia Chu, Lori Kunselman, Liqun Gu, Randolph Ponticiello, Michael Cap, Fucheng Qu, Chunning Shao, [......], Wen-Pin Yang, Jimmy Ren, Min Zhou, Denis Ryono, Scott Biller, Kasim A Mookhtiar, John Wetterau, Richard Gregg, Peter T Cheng, Narayanan Hariharan
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  ABSTRACT: Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/db mice. In db/db mice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/db mice, muraglitazar treatment (0.03-50 mg . kg(-1) . day(-1) for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/db mice, longer-term muraglitazar treatment (30 mg . kg(-1) . day(-1) for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/db mice, muraglitazar treatment (10 mg . kg(-1) . day(-1) for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high-molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/db mice. The overall conclusions are that in db/db mice, the novel dual (alpha/gamma) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.
  Diabetes 02/2006; 55(1):240-8. · 8.29 Impact Factor
• Article: Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a novel peroxisome proliferator-activated receptor alpha/gamma dual agonist with efficacious glucose and lipid-lowering activities.

  Pratik V Devasthale, Sean Chen, Yoon Jeon, Fucheng Qu, Chunning Shao, Wei Wang, Hao Zhang, Michael Cap, Dennis Farrelly, Rajasree Golla, [......], Arthur Doweyko, Gamini Chandrasena, Shu Y Chang, W Griffith Humphreys, Vito G Sasseville, Scott A Biller, Denis E Ryono, Fred Selan, Narayanan Hariharan, Peter T W Cheng
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  ABSTRACT: Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.
  Journal of Medicinal Chemistry 04/2005; 48(6):2248-50. · 5.25 Impact Factor
• Article: Design and Synthesis of N-[(4-Methoxyphenoxy)carbonyl]-N-[[4-[2-(5- methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine [Muraglitazar/BMS-298585], a Novel Peroxisome Proliferator-Activated Receptor α/γ Dual Agonist with Efficacious Glucose and Lipid-Lowering Activities

  Pratik V. Devasthale, Sean Chen, Yoon Jeon, Fucheng Qu, Chunning Shao, Wei Wang, Hao Zhang, Michael Cap, Dennis Farrelly, Rajasree Golla, [......], Arthur Doweyko, Gamini Chandrasena, Shu Y. Chang, W. Griffith Humphreys, Vito G. Sasseville, Scott A. Biller, Denis E. Ryono, Fred Selan, Narayanan Hariharan, Peter T. W. Cheng
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  ABSTRACT: Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR α/γ dual agonist that shows potent activity in vitro at human PPARα (EC50 = 320 nM) and PPARγ (EC50 = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.
  11/2004;
• Article: Discovery of azetidinone acids as conformationally-constrained dual PPARα/γ agonists

  Wei Wang, Pratik Devasthale, Dennis Farrelly, Liqun Gu, Thomas Harrity, Michael Cap, Cuixia Chu, Lori Kunselman, Nathan Morgan, Randy Ponticiello, [......], Vinayak Hosagrahara, Lisa Zhang, Pathanjali Kadiyala, Chiehying Chang, Jodi Muckelbauer, Arthur M. Doweyko, Robert Zahler, Denis Ryono, Narayanan Hariharan, Peter T.W. Cheng
  Bioorganic & Medicinal Chemistry Letters. 18(6):1939-1944.