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10.1021/acs.jmedchem.5b01685 http://scihub22266oqcxt.onion/10.1021/acs.jmedchem.5b01685 C5362750!5362750 !26796641     free     free     free Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 235.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 269.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\26796641 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       J+Med+Chem 2016 ; 59 (3 ): 1078-101 Nephropedia Template TP {{tp|p=26796641 |t=2016. Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19 |pdf=|usr=}}{{26796641 }} gab.com Text Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19 JO: J Med Chem http://www.kidney.de/pget.php?&tw=1&pmid=26796641 #FOAvip The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer. Twit Text FOAVip Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19 ????J Med Chem http://www.kidney.de/pget.php?&tw=1&pmid=26796641 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=26796641 #FOAvip English Wikipedia <ref>{{Cite pmid|26796641 }}</ref> Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19 #MMPMID26796641 Mallinger A ; Schiemann K ; Rink C ; Stieber F ; Calderini M ; Crumpler S ; Stubbs M ; Adeniji-Popoola O ; Poeschke O ; Busch M ; Czodrowski P ; Musil D ; Schwarz D ; Ortiz-Ruiz MJ ; Schneider R ; Thai C ; Valenti M ; de Haven Brandon A ; Burke R ; Workman P ; Dale T ; Wienke D ; Clarke PA ; Esdar C ; Raynaud FI ; Eccles SA ; Rohdich F ; Blagg J J Med Chem 2016[Feb]; 59 (3 ): 1078-101 PMID26796641 show ga The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer. |*Drug Discovery [MESH] |Administration, Oral [MESH] |Aminopyridines/administration & dosage/chemistry/*pharmacology [MESH] |Animals [MESH] |Biological Availability [MESH] |Caco-2 Cells [MESH] |Cyclin-Dependent Kinase 8/*antagonists & inhibitors/metabolism [MESH] |Cyclin-Dependent Kinases/*antagonists & inhibitors/metabolism [MESH] |Dogs [MESH] |Dose-Response Relationship, Drug [MESH] |Female [MESH] |Humans [MESH] |Male [MESH] |Mice [MESH] |Models, Molecular [MESH] |Molecular Structure [MESH] |Neoplasms, Experimental/drug therapy/pathology [MESH] |Rats [MESH] |Rats, Wistar [MESH] |Small Molecule Libraries/administration & dosage/chemistry/*pharmacology [MESH] |Solubility [MESH] |Structure-Activity Relationship [MESH]Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule(epmc).pdf DeepDyve Pubget Overpricing