3rtp
Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegenerationDesign and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration
Structural highlights
Disease[MK10_HUMAN] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. Function[MK10_HUMAN] Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.[1] Publication Abstract from PubMedThe 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. Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration.,Bowers S, Truong AP, Jeffrey Neitz R, Hom RK, Sealy JM, Probst GD, Quincy D, Peterson B, Chan W, Galemmo RA Jr, Konradi AW, Sham HL, Toth G, Pan H, Lin M, Yao N, Artis DR, Zhang H, Chen L, Dryer M, Samant B, Zmolek W, Wong K, Lorentzen C, Goldbach E, Tonn G, Quinn KP, Sauer JM, Wright S, Powell K, Ruslim L, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2011 Sep 15;21(18):5521-7. doi: 10.1016/j.bmcl.2011.06.100., Epub 2011 Jul 7. PMID:21813278[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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