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Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors.

Zheng K, Park CM, Iqbal S, Hernandez P, Park H, LoGrasso PV, Feng Y
ACS Med Chem Lett 6 413-8 (2015)
Cited: 8 times
EuropePMC logo PMID: 25893042

Abstract

A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure-activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t 1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 Å. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.

Reviews - 4y5h mentioned but not cited (1)

  1. C-Jun N-terminal kinase inhibitors: Structural insight into kinase-inhibitor complexes. Duong MTH, Lee JH, Ahn HC. Comput Struct Biotechnol J 18 1440-1457 (2020)

Articles - 4y5h mentioned but not cited (2)

  1. Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells. Kim NY, Vishwanath D, Xi Z, Nagaraja O, Swamynayaka A, Kumar Harish K, Basappa S, Madegowda M, Pandey V, Sethi G, Lobie PE, Ahn KS, Basappa B. Molecules 28 3450 (2023)
  2. Essential Oils from the Leaves, Stem, and Roots of Blumea lanceolaria (Roxb.) Druce in Vietnam: Determination of Chemical Composition, and In Vitro, In Vivo, and In Silico Studies on Anti-Inflammatory Activity. Do TTH, Nguyen TU, Nguyen TTH, Ho TY, Pham TLH, Le TS, Nguyen THV, Nguyen PH, Nguyen QH, Nguyen VS. Molecules 27 7839 (2022)


Reviews citing this publication (1)

  1. Selective inhibitors for JNK signalling: a potential targeted therapy in cancer. Wu Q, Wu W, Jacevic V, Franca TCC, Wang X, Kuca K. J Enzyme Inhib Med Chem 35 574-583 (2020)

Articles citing this publication (4)

  1. Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors. Feng Y, Park H, Bauer L, Ryu JC, Yoon SO. ACS Med Chem Lett 12 24-29 (2021)
  2. Epidrugs in Amyotrophic Lateral Sclerosis/Frontotemporal Dementia: Contextualizing a Role for Histone Kinase Inhibition in Neurodegenerative Disease. Cobos SN, Torrente MP. ACS Pharmacol Transl Sci 5 134-137 (2022)
  3. Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain. Scott JA, Soto-Velasquez M, Hayes MP, LaVigne JE, Miller HR, Kaur J, Ejendal KFK, Watts VJ, Flaherty DP. J Med Chem 65 4667-4686 (2022)
  4. N-Aromatic-Substituted Indazole Derivatives as Brain-Penetrant and Orally Bioavailable JNK3 Inhibitors. Feng Y, Park H, Ryu JC, Yoon SO. ACS Med Chem Lett 12 1546-1552 (2021)


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