- Process development on the enantioselective enzymatic hydrolysis of S-ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate
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A novel biocatalytic approach for the large-scale production of S-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid S-1 from its racemic ethylester rac-2 by enantioselective hydrolysis has been developed. S-1 is an important building block in the synthesis of PPARα and -γ agonists such as Ragaglitazar [NNC 61-0029 ((-)DRF2725)]. The development history comprises enzyme screening, biocatalyst and process optimization, and scale-up to pilot plant. The project was thereby highly interdisciplinary by combining biotechnology and chemistry technologies. The final process was successfully run on a 44-kg pilot scale in 43-48% yields and with high enantiomeric purities (98.4-99.6% ee).
- Deussen, Heinz-Josef,Zundel, Magali,Valdois, Marine,Lehmann, Soren Vig,Weil, Volker,Mailand Hjort, Carsten,stergaard, Peter Rahbek,Marcussen, Erik,Ebdrup, Soren
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Read Online
- PYRIMIDINYL-PROPIONIC ACID DERIVATIVES AND THEIR USE AS PPAR AGONISTS
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The present invention disclosed compounds of Structural Formula (I), and enantiomer, racemic body, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein variable groups are as defined within, as well as methods for preparing such compou
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Page/Page column 12-13
(2010/10/03)
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- NOVEL PHENYLPROPIONIC ACID DERIVATIVES AS PEROXISOME PROLIFERATOR-ACTIVATED GAMMA RECEPTOR MODULATORS, METHOD OF THE SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention provides a novel phenylpropionic acid derivative and a PPAR-γ modulator comprising the same as an active ingredient. The phenylpropionic acid derivative of the present invention has modulatory action on function of PPAR-γ and then exhibits hypoglycemic, hypolipidemic and insulin resistance-reducing effects on PPAR-mediated diseases or disorders. Therefore, the present invention is prophylactically or therapeutically effective for diabetes and metabolic diseases.
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Page/Page column 29
(2010/04/23)
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- PYRIMIDINYL-PROPIONIC ACID DERIVATIVES AND THEIR USE AS PPAR AGONISTS
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The present invention disclosed compounds of Structural Formula (I), and enantiomer, racemic body, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein variable groups are as defined within, as well as methods for preparing such compou
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Page/Page column 17-18
(2009/05/30)
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- 4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARα/γ agonists. Part I: Synthesis and pharmacological evaluation
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Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a defect in pancreatic β-cell. Since their discovery three subtypes of Peroxisomes Proliferators Activated Receptors were identified namely PPARα, PPARγ and PPARβ/(δ). We were interested in designing novel PPARγ selective agonists and/or dual PPARα/γ agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as novel cyclic tail.
- Parmenon, Cecile,Guillard, Jerome,Caignard, Daniel-Henri,Hennuyer, Nathalie,Staels, Bart,Audinot-Bouchez, Valerie,Boutin, Jean-Albert,Dacquet, Catherine,Ktorza, Alain,Viaud-Massuard, Marie-Claude
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p. 1617 - 1622
(2008/09/19)
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- NOVEL PHENYLPROPIONIC ACID DERIVATIVES AS PEROXISOME PROLIFERATOR-ACTIVATED GAMMA RECEPTOR MODULATORS, METHOD OF THE SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention provides a novel phenylpropionic acid derivative and a PPAR-γ modulator comprising the same as an active ingredient. The phenylpropionic acid derivative of the present invention has modulatory action on function of PPAR-γ and then exhibits hypoglycemic, hypolipidemic and insulin resistance-reducing effects on PPAR-mediated diseases or disorders. Therefore, the present invention is prophylactically or therapeutically effective for diabetes and metabolic diseases.
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Page/Page column 44; 27
(2008/12/08)
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- Design, synthesis, and structure-activity relationship of carbamate-tethered aryl propanoic acids as novel PPARα/γ dual agonists
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We have developed a new class of PPARα/γ dual agonists, which show excellent agonistic activity in PPARα/γ transactivation assay. In particular, (R)-9d was identified as a potent PPARα/γ dual agonist with EC50s of 0.377 μM in PPARα and 0.136 μM in PPARγ, respectively. Interestingly, the structure-activity relationship revealed that the stereochemistry of the identified PPARα/γ dual agonists significantly affects their agonistic activities in PPARα than in PPARγ.
- Kim, Nam-Jung,Lee, Kwang-Ok,Koo, Bon-Woong,Li, Funan,Yoo, Ja-Kyung,Park, Hyun-Ju,Min, Kyung-Hoon,Lim, Joong In,Kim, Mi Kyung,Kim, Jin-Kwan,Suh, Young-Ger
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p. 3595 - 3598
(2008/02/11)
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- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
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Page/Page column 45
(2008/06/13)
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- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
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Page/Page column 29
(2010/11/27)
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- Design, synthesis, and evaluation of 2-alkoxydihydrocinnamates as PPAR agonists
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A series of 2-alkoxydihydrocinnamates were synthesized as PPARγ and PPARα dual agonists. In vitro studies in cell model showed that these compounds were efficacious. Compound 1g was found to be a potent PPARα/γ dual agonist and will be further evaluated for the treatment of type II diabetes.
- Lu, Ying,Guo, Zongru,Guo, Yanshen,Feng, Jun,Chu, Fengming
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p. 915 - 919
(2007/10/03)
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- Synthesis and biological activity of novel α-substituted β-phenylpropionic acids having pyridin-2-ylphenyl moiety as antihyperglycemic agents
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We previously reported the identification of novel oximes having 5-benzyl-2,4-thiazolidinedione with antihyperglycemic activity. We now report the synthesis and biological activity of a novel series of oximes and amides having α-substituted-β-phenylpropionic acids. In this series, we obtained potent PPARα/γ dual agonist (S)-9d, with which activation of PPARα and PPARγ was considerably more potent than that of the reference compounds GW9578 22 and rosiglitazone 3, respectively. This means (S)-9d is of the strongest class of PPARα/γ dual agonists. In the course of this study, we also obtained 8h, which indicated potent plasma glucose lowering effect in spite of weak PPARα/γ agonistic activity.
- Takamura, Makoto,Sakurai, Mitsuya,Yamada, Eriko,Fujita, Sachie,Yachi, Makoto,Takagi, Toshiyuki,Isobe, Aya,Hagisawa, Yuka,Fujiwara, Toshihiko,Yanagisawa, Hiroaki
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p. 2419 - 2439
(2007/10/03)
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- Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor α/γ agonist ragaglitazar
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A new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist ragaglitazar applicable for large-scale preparation has been developed. The convergent synthetic procedure was based on a novel enzymatic kinetic resolution step
- Ebdrup, S?ren,Pettersson, Ingrid,Rasmussen, Hanne B.,Deussen, Heinz-Josef,Jensen, Anette Frost,Mortensen, Steen B.,Fleckner, Jan,Pridal, Lone,Nygaard, Lars,Sauerberg, Per
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p. 1306 - 1317
(2007/10/03)
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- Novel thieno oxazine analogues as antihyperglycemic and lipid modulating agents
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A series of phenyl acetic acid and α-hydroxy propionic acid derivatives were synthesized. In vivo studies of the compounds indicated compound 2c as the most potent in one of the series, which has both glucose and lipid lowering properties. The syntheses and biological studies have been discussed.
- Das, Saibal Kumar,Reddy, K. Anantha,Abbineni, Chandrasekhar,Iqbal, Javed,Suresh,Premkumar,Chakrabarti, Ranjan
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p. 399 - 403
(2007/10/03)
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- Phenalkyloxy-phenyl derivatives
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The present invention relates to certain phenalkyloxy-phenyl derivatives of formula (I) and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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- Quinoline derivatives and medicinal use thereof
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A quinoline derivative represented by the following formula (1): allows PPARα or γ which is an intranuclear transcription factor, to function strongly and is low in toxicity. By using this compound as an active ingredient, there can be provided a preventive or therapeutic agent for various diseases related to PPARα or γ.
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- 3-aryl-2-hydroxypropionic acid derivative III
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A novel 3-aryl-2-hydroxypropionic acid derivative, a process and intermediate for its manufacture, pharmaceutical prepartions containing it and the use of the compound in clinical conditions associated with insulin resistance.
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