Discovery of pyrrolo[1,2-b]pyridazine-3-carboxamides as Janus kinase (JAK) inhibitors

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5721-5726. doi: 10.1016/j.bmcl.2014.10.061. Epub 2014 Oct 24.

Abstract

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

Keywords: JAK inhibitor; JAK3; Janus kinase; Pyrrolo[1,2-b]pyridazine; TYK2.

MeSH terms

  • Administration, Oral
  • Animals
  • Drug Discovery*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Interferon-gamma / metabolism
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Janus Kinase 3 / antagonists & inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Structure
  • Protein Conformation / drug effects
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridazines / chemistry*
  • Pyrroles / chemistry*
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Protein Kinase Inhibitors
  • Pyridazines
  • Pyrroles
  • Pyrrolopyridazine
  • Interferon-gamma
  • JAK1 protein, human
  • JAK2 protein, human
  • JAK3 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3