Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): Kinase profiling guided optimization of a 1, 2, 3-benzotriazole lead

…, DM Goldstein, L Gong, B Goyal, JC Hermann…

Index: Palmer, Wylie S.; Alam, Muzaffar; Arzeno, Humberto B.; Chang, Kung-Ching; Dunn, James P.; Goldstein, David M.; Gong, Leyi; Goyal, Bindu; Hermann, Johannes C.; Hogg, J. Heather; Hsieh, Gary; Jahangir, Alam; Janson, Cheryl; Jin, Sue; Ursula Kammlott; Kuglstatter, Andreas; Lukacs, Christine; Michoud, Christophe; Niu, Linghao; Reuter, Deborah C.; Shao, Ada; Silva, Tania; Trejo-Martin, Teresa A.; Stein, Karin; Tan, Yun-Chou; Tivitmahaisoon, Parcharee; Tran, Patricia; Wagner, Paul; Weller, Paul; Wu, Shao-Yong Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 5 p. 1486 - 1492

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Citation Number: 12

Abstract

A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1, 2, 3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC50= 16 and 66nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.