Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479 (Englisch)
- Neue Suche nach: Robarge, Kirk D.
- Neue Suche nach: Lee, Wendy
- Neue Suche nach: Eigenbrot, Charles
- Neue Suche nach: Ultsch, Mark
- Neue Suche nach: Wiesmann, Christian
- Neue Suche nach: Heald, Robert
- Neue Suche nach: Price, Steve
- Neue Suche nach: Hewitt, Joanne
- Neue Suche nach: Jackson, Philip
- Neue Suche nach: Savy, Pascal
- Neue Suche nach: Burton, Brenda
- Neue Suche nach: Choo, Edna F.
- Neue Suche nach: Pang, Jodie
- Neue Suche nach: Boggs, Jason
- Neue Suche nach: Yang, April
- Neue Suche nach: Yang, Xioaye
- Neue Suche nach: Baumgardner, Matthew
- Neue Suche nach: Robarge, Kirk D.
- Neue Suche nach: Lee, Wendy
- Neue Suche nach: Eigenbrot, Charles
- Neue Suche nach: Ultsch, Mark
- Neue Suche nach: Wiesmann, Christian
- Neue Suche nach: Heald, Robert
- Neue Suche nach: Price, Steve
- Neue Suche nach: Hewitt, Joanne
- Neue Suche nach: Jackson, Philip
- Neue Suche nach: Savy, Pascal
- Neue Suche nach: Burton, Brenda
- Neue Suche nach: Choo, Edna F.
- Neue Suche nach: Pang, Jodie
- Neue Suche nach: Boggs, Jason
- Neue Suche nach: Yang, April
- Neue Suche nach: Yang, Xioaye
- Neue Suche nach: Baumgardner, Matthew
In:
Bioorganic and Medicinal Chemistry Letters
;
24
, 19
;
4714-4723
;
2014
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ISSN:
- Aufsatz (Zeitschrift) / Elektronische Ressource
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Titel:Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479
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Beteiligte:Robarge, Kirk D. ( Autor:in ) / Lee, Wendy ( Autor:in ) / Eigenbrot, Charles ( Autor:in ) / Ultsch, Mark ( Autor:in ) / Wiesmann, Christian ( Autor:in ) / Heald, Robert ( Autor:in ) / Price, Steve ( Autor:in ) / Hewitt, Joanne ( Autor:in ) / Jackson, Philip ( Autor:in ) / Savy, Pascal ( Autor:in )
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Erschienen in:Bioorganic and Medicinal Chemistry Letters ; 24, 19 ; 4714-4723
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Verlag:
- Neue Suche nach: Elsevier Ltd
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Erscheinungsdatum:05.08.2014
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Format / Umfang:10 pages
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ISSN:
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DOI:
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Medientyp:Aufsatz (Zeitschrift)
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Format:Elektronische Ressource
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Sprache:Englisch
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Schlagwörter:MAPK/ERK kinase (MEK) signaling cascade , The pathway includes many proteins, including MAPK (mitogen-activated protein kinases, originally called ERK, extracellular signal-regulated kinases), which communicate by adding phosphate groups to a neighboring protein, which acts as an ‘on’ or ‘off’ switch. Also known as the RAS-RAF-MEK-ERK mitogen-activated protein kinase signaling pathway , KRAS , GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene , NRAS , The N-ras oncogene is a member of the Ras gene family and an enzyme that in humans is encoded by the NRAS gene. It was named NRAS for its initial identification in human neuroblastoma cells , HRAS , GTPase HRas also known as transforming protein p21 is an enzyme that in humans is encoded by the HRAS gene. Once bound to guanosine triphosphate, activates a Raf kinase like c-Raf, the next step in the MAPK/ERK signaling cascade , BRAF , BRAF is a human gene that makes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf , RAF , proto-oncogene serine/threonine-protein kinase also known as c-RAF , AKT , AKT is also known as protein kinase B(PKB), is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration , PI3K , phosphatidylinositol-4,5-bisphosphate 3-kinase are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer , MEKi’s , MAPK/ERK kinase (MEK) signaling cascade inhibitors. A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. Allosteric MEK inhibitors described herein inhibit both MEK1 and MEK 2 , MEK 1,2 inhibitors , MEK 1,2 inhibitors are synonymous with MEKi’s , ATP , adenosine triphosphate is a nucleoside triphosphate used in cells as a coenzyme , H-bond , hydrogen bond , BID , twice daily , QD , once daily , CYP , cytochrome P450 , log D (measured) , distribution-coefficient is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium. These coefficients are a measure of the difference in solubility of the compound in these two phases. Log D’s have a pH dependence. Log D measurements for MEKi’s disclosed herein were performed at pH 7.4 , c log D , calculated log D @ pH 7.4 , c log P , calculated partition-coefficient (c log P) is the calculated ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium. These coefficients are a measure of the difference in solubility of the compound in these two phases. The c log P value reflects the overall lipophilicity of a molecule , IV , delivered directly into the vein , PO , by mouth , Mic(H/R/M/D/C) , Microsomes H(human)/R(rat)/M(mouse)/D(dog)/C(cyno). Incubation of the MEKi’s described herein was conducted with liver microsomes from human(HLM) and pre-clinical species rat(RLM), mouse(MLM), dog(DLM), and cyno(CLM) to assess comparative metabolic stability , PEG 400 , polyethylene glycol 400 is a low-molecular-weight grade of polyethylene glycol miscible with water and used as vehicle for dosing rats IV and PO , CLp , In vivo total plasma clearance is defined as the volume of blood or plasma cleared of drug in a unit time. It is related to the volume in which the drug is dissolved and the rate at which it is eliminated , T 1/2 (h) , half life of MEK inhibitor when dosed intravenously , ppb , plasma protein binding , Oral exposure , area under the plasma concentration versus time curve (AUC) , %F , oral bioavailability which is the dose-corrected area under curve (AUC) after oral dosing divided by AUC intravenous , IV/IV , in vitro/in vivo clearance correlation (CL predicted from rat microsome incubation/versus CL observed after intravenous administration in rat) , Mitogen-activated protein kinase kinase inhibitors , MEK inhibitors , RAS signaling pathway , Imidazo[1,5-a] pyrazine , Imidazo[1,5-a] pyridine , Structure based drug design (SBDD) , Oncology
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Datenquelle:
Inhaltsverzeichnis – Band 24, Ausgabe 19
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