- Synthesis, Identification, and Structure-Activity Relationship Analysis of GATA4 and NKX2-5 Protein-Protein Interaction Modulators
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Transcription factors GATA4 and NKX2-5 directly interact and synergistically activate several cardiac genes and stretch-induced cardiomyocyte hypertrophy. Previously, we identified phenylisoxazole carboxamide 1 as a hit compound, which inhibited the GATA4-NKX2-5 transcriptional synergy. Here, the chemical space around the molecular structure of 1 was explored by synthesizing and characterizing 220 derivatives and structurally related compounds. In addition to the synergistic transcriptional activation, selected compounds were evaluated for their effects on transcriptional activities of GATA4 and NKX2-5 individually as well as potential cytotoxicity. The structure-activity relationship (SAR) analysis revealed that the aromatic isoxazole substituent in the southern part regulates the inhibition of GATA4-NKX2-5 transcriptional synergy. Moreover, inhibition of GATA4 transcriptional activity correlated with the reduced cell viability. In summary, comprehensive SAR analysis accompanied by data analysis successfully identified potent and selective inhibitors of GATA4-NKX2-5 transcriptional synergy and revealed structural features important for it.
- Jumppanen, Mikael,Kinnunen, Sini M.,V?lim?ki, Mika J.,Talman, Virpi,Auno, Samuli,Bruun, Tanja,Boije Af Genn?s, Gustav,Xhaard, Henri,Aumüller, Ingo B.,Ruskoaho, Heikki,Yli-Kauhaluoma, Jari
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supporting information
p. 8284 - 8310
(2019/10/11)
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- TREAMENT FOR CHEMICAL SUBSTANCE ADDICTION
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The present invention provides a method for the treatment of chemical substance abuse by selectively inhibiting ghrelin activity in humans comprising administering to a human in need thereof a therapeutically-effective amount of a ghrelin receptor ligand (GHS-RL). The ghrelin receptor ligand (GHS-RL) can be selected from the group consisting of a ghrelin receptor antagonist (GHS-RA), a ghrelin receptor inverse agonist (GHS-RIA), and a ghrelin receptor partial agonist (GHS-RPA). More specifically, the invention provides a method for treating alcohol related disorders in humans comprising administering to a human in need thereof a therapeutically-effective amount of a compound which is a ghrelin receptor ligand (GHS-RL), such as a ghrelin receptor antagonist (GHS-RA), a ghrelin receptor inverse agonist (GHS-RIA) and a ghrelin receptor partial agonist (GHS-RPA).
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- Isoxazole carboxamide derivatives as ghrelin receptor modulators
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The present invention is related to compounds of formula (I), or a therapeutically suitable salt or prodrug thereof, the preparation of the compounds, compositions containing the compounds and the use of the compounds in the prevention or treatment of disorders regulated by ghrelin including anorexia, cancer cachexia, eating disorders, age-related decline in body composition, weight gain, obesity, and diabetes mellitus.
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Page/Page column 12
(2010/11/08)
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- Synthesis and structure-activity relationships of isoxazole carboxamides as growth hormone secretagogue receptor antagonists
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A series of isoxazole carboxamide derivatives has been developed as potent ghrelin receptor antagonists. The synthesis and structure-activity relationship (SAR) are described.
- Xin, Zhili,Zhao, Hongyu,Serby, Michael D.,Liu, Bo,Schaefer, Verlyn G.,Falls, Douglas H.,Kaszubska, Wiweka,Colins, Christine A.,Sham, Hing L.,Liu, Gang
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p. 1201 - 1204
(2007/10/03)
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- Discovery of tetralin carboxamide growth hormone secretagogue receptor antagonists via scaffold manipulation
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A case study of rational design of an efficient, specific, and proprietary molecular scaffold based on the structure-activity relationship (SAR) information on a screening hit is described. Potent, selective, and orally bioavailable tetralin carboxamide g
- Zhao, Hongyu,Xin, Zhili,Liu, Gang,Schaefer, Verlyn G.,Falls, H. Douglas,Kaszubska, Wiweka,Collins, Christine A.,Sham, Hing L.
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p. 6655 - 6657
(2007/10/03)
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- Novel isoxazole carboxamides as growth hormone secretagogue receptor (GHS-R) antagonists
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Novel isoxazole carboxamides have been identified as growth hormone secretagogue receptor (GHS-R) antagonists. Substituent modification off the 5-position of the isoxazole ring led to analogues with potent binding affinity and functional antagonism of GHS-R. A potent analogue (32) with high aqueous solubility and good GPCR selectivity was also identified as a potential pharmacological tool for in vivo studies.
- Liu, Bo,Liu, Gang,Xin, Zhili,Serby, Micheal D.,Zhao, Hongyu,Schaefer, Verlyn G.,Falls, H. Douglas,Kaszubska, Wiweka,Collins, Christine A.,Sham, Hing L.
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p. 5223 - 5226
(2007/10/03)
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