Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration

The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which lead to compounds such as 42 with lower clearance, grea...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-09, Vol.21 (18), p.5521-5527
Hauptverfasser:	Bowers, Simeon, Truong, Anh P., Jeffrey Neitz, R., Hom, Roy K., Sealy, Jennifer M., Probst, Gary D., Quincy, David, Peterson, Brian, Chan, Wayman, Galemmo, Robert A., Konradi, Andrei W., Sham, Hing L., Tóth, Gergely, Pan, Hu, Lin, May, Yao, Nanhua, Artis, Dean R., Zhang, Heather, Chen, Linda, Dryer, Mark, Samant, Bhushan, Zmolek, Wes, Wong, Karina, Lorentzen, Colin, Goldbach, Erich, Tonn, George, Quinn, Kevin P., Sauer, John-Michael, Wright, Sarah, Powell, Kyle, Ruslim, Lany, Ren, Zhao, Bard, Frédérique, Yednock, Ted A., Griswold-Prenner, Irene
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Biological and medical sciences brain Brain - metabolism c-Jun N-terminal kinase inhibitor Chemistry Techniques, Synthetic Crystallography, X-Ray Dose-Response Relationship, Drug Drug Design Half-Life JNK JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors JNK Mitogen-Activated Protein Kinases - metabolism Medical sciences metabolites Mice mitogen-activated protein kinase Models, Molecular Molecular Structure Nerve Degeneration - prevention & control Neurodegeneration Neuropharmacology Neuroprotective agent pharmacokinetics Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Stereoisomerism Structure-Activity Relationship thiophene Thiophenes - chemical synthesis Thiophenes - chemistry Thiophenes - pharmacokinetics Thiophenes - pharmacology Trisubstituted thiophene
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Zusammenfassung:	The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which lead to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs. The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.06.100