Details

Autor(en) / Beteiligte

• Probst, Gary D.
• Bowers, Simeon
• Sealy, Jennifer M.
• Truong, Anh P.
• Hom, Roy K.
• Galemmo, Robert A.
• Konradi, Andrei W.
• Sham, Hing L.
• Quincy, David A.
• Pan, Hu
• Yao, Nanhua
• Lin, May
• Tóth, Gergley
• Artis, Dean R.
• Zmolek, Wes
• Wong, Karina
• Qin, Ann
• Lorentzen, Colin
• Nakamura, David F.
• Quinn, Kevin P.
• Sauer, John-Michael
• Powell, Kyle
• Ruslim, Lany
• Wright, Sarah
• Chereau, David
• Ren, Zhao
• Anderson, John P.
• Bard, Frédérique
• Yednock, Ted A.
• Griswold-Prenner, Irene

Titel

Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2011-01, Vol.21 (1), p.315-319

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors. In this Letter, we describe the discovery of selective JNK2 and JNK3 inhibitors, such as 10, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs, p38α and ERK2. Substitution of the naphthalene ring affords an isoform selective JNK3 inhibitor, 30, with approximately 10-fold selectivity over both JNK1 and JNK2. A naphthalene ring penetrates deep into the selectivity pocket accounting for the differentiation amongst the kinases. Interestingly, the gatekeeper Met146 sulfide interacts with the naphthalene ring in a sulfur-π stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-β in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.