Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration.
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Probst GD, Bowers S, Sealy JM, Truong AP, Hom RK, Galemmo RA Jr, Konradi AW, Sham HL, Quincy DA, Pan H, Yao N, Lin M, Toth G, Artis DR, Zmolek W, Wong K, Qin A, Lorentzen C, Nakamura DF, Quinn KP, Sauer JM, Powell K, Ruslim L, Wright S, Chereau D, Ren Z, Anderson JP, Bard F, Yednock TA, Griswold-Prenner I
Highly selective c-Jun N-terminal kinase (JNK) 2 and 3 inhibitors with in vitro CNS-like pharmacokinetic properties prevent neurodegeneration.
Bioorg Med Chem Lett. 2011 Jan 1;21(1):315-9. doi: 10.1016/j.bmcl.2010.11.010. Epub 2010 Nov 5.
- PubMed ID
- 21112785 [ View in PubMed]
- Abstract
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, p38alpha 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-pi stacking interaction. Compound 38 ameliorates neurotoxicity induced by amyloid-beta in human cortical neurons. Lastly, we demonstrate how to install propitious in vitro CNS-like properties into these selective inhibitors.
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- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Cyclohexyl-{4-[5-(3,4-Dichlorophenyl)-2-Piperidin-4-Yl-3-Propyl-3h-Imidazol-4-Yl]-Pyrimidin-2-Yl}Amine Mitogen-activated protein kinase 10 IC 50 (nM) 1.6 N/A N/A Details