Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1

Bioorg Med Chem. 2020 May 15;28(10):115481. doi: 10.1016/j.bmc.2020.115481. Epub 2020 Mar 31.

Abstract

Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.

Keywords: Arthritis; Autoimmune; Inflammation; JAK1; Kinase; Psoriasis; TYK2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Female
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 1 / metabolism
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Structure-Activity Relationship
  • TYK2 Kinase / antagonists & inhibitors*
  • TYK2 Kinase / metabolism

Substances

  • Protein Kinase Inhibitors
  • JAK1 protein, human
  • Janus Kinase 1
  • TYK2 Kinase
  • TYK2 protein, human