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Pyridopyrimidinone derivatives as potent and selective c-jun N-terminal kinase (JNK) inhibitors

Academic Article
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Overview

authors

  • Zheng, K.
  • Park, C. M.
  • Iqbal, S.
  • Hernandez, P.
  • Park, HaJeung
  • LoGrasso, Philip
  • Feng, Yangbo

publication date

  • April 2015

journal

  • ACS Medicinal Chemistry Letters  Journal

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.
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Research

keywords

  • JNK3
  • Parkinson's disease (PD)
  • kinase inhibitor
  • mitochondrial dysfunction
  • pyridopyrimidinone
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Identity

PubMed Central ID

  • PMC4394340

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml500474d

PubMed ID

  • 25893042
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Additional Document Info

start page

  • 413

end page

  • 418

volume

  • 6

issue

  • 4

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