Synthesis and SAR Studies of 1 H-Pyrrolo[2,3- b]pyridine-2-carboxamides as Phosphodiesterase 4B (PDE4B) Inhibitors

Anish K. Vadukoot, Swagat Sharma, Christopher D. Aretz, Sushil Kumar, Nagsen Gautam, Yazen Alnouti, Amy L. Aldrich, Cortney E. Heim, Tammy Kielian, Corey R. Hopkins

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Herein we report the synthesis, SAR, and biological evaluation of a series of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives as selective and potent PDE4B inhibitors. Compound 11h is a PDE4B preferring inhibitor and exhibited acceptable in vitro ADME and significantly inhibited TNF-α release from macrophages exposed to pro-inflammatory stimuli (i.e., lipopolysaccharide and the synthetic bacterial lipopeptide Pam3Cys). In addition, 11h was selective against a panel of CNS receptors and represents an excellent lead for further optimization and preclinical testing in the setting of CNS diseases.

Original languageEnglish (US)
Pages (from-to)1848-1854
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume11
Issue number10
DOIs
StatePublished - Oct 8 2020

Keywords

  • 1H-Pyrrolo[2,3- b]pyridine-2-carboxamide
  • PDE4B
  • phosphodiesterase 4
  • scaffold hopping

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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