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InCl3 mediated heteroarylation of indoles and their derivatization via CH activation strategy: Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis.

Abstract
A new class of PDE4 inhibitors were designed and synthesized via the InCl3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed CH activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC50 = 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively) showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) in Zebrafish.
AuthorsRajnikanth Sunke, Ramudu Bankala, B Thirupataiah, E V V Shivaji Ramarao, Jetta Sandeep Kumar, Hari Maduri Doss, Raghavender Medishetti, Pushkar Kulkarni, Ravi Kumar Kapavarapu, Mahaboobkhan Rasool, Jayesh Mudgal, Jessy E Mathew, Gautham G Shenoy, Kishore V L Parsa, Manojit Pal
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 174 Pg. 198-215 (Jul 15 2019) ISSN: 1768-3254 [Electronic] France
PMID31035240 (Publication Type: Journal Article)
CopyrightCopyright © 2019 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Indoles
  • Oligodendrocyte-Myelin Glycoprotein
  • Phosphodiesterase 4 Inhibitors
  • Quinoxalines
  • Zebrafish Proteins
  • Indium
  • indium trichloride
  • Freund's Adjuvant
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, rat
Topics
  • Animals
  • Arthritis (drug therapy)
  • Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
  • Encephalomyelitis, Autoimmune, Experimental (chemically induced, drug therapy)
  • Freund's Adjuvant
  • Indium
  • Indoles (chemical synthesis, chemistry, therapeutic use, toxicity)
  • Molecular Structure
  • Multiple Sclerosis (chemically induced, drug therapy)
  • Oligodendrocyte-Myelin Glycoprotein
  • Phosphodiesterase 4 Inhibitors (chemical synthesis, chemistry, therapeutic use, toxicity)
  • Quinoxalines (chemical synthesis, chemistry, therapeutic use, toxicity)
  • Rats
  • Structure-Activity Relationship
  • Zebrafish
  • Zebrafish Proteins (metabolism)

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