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

…, D Quincy, B Peterson, W Chan, RA Galemmo…

Index: Bowers, Simeon; Truong, Anh P.; Jeffrey Neitz; Hom, Roy K.; Sealy, Jennifer M.; Probst, Gary D.; Quincy, David; Peterson, Brian; Chan, Wayman; Galemmo Jr., Robert A.; Konradi, Andrei W.; Sham, Hing L.; Toth, 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, Frederique; Yednock, Ted A.; Griswold-Prenner, Irene Bioorganic and Medicinal Chemistry Letters, 2011 , vol. 21, # 18 p. 5521 - 5527

Full Text: HTML

Citation Number: 17

Abstract

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.