Identification of novel azaindazole CCR1 antagonist clinical candidates

  • Bioorg Med Chem Lett. 2019 Feb 1;29(3):441-448. doi: 10.1016/j.bmcl.2018.12.024.
Christian Harcken  1 ,  Daniel Kuzmich  2 ,  Brain Cook  2 ,  Can Mao  2 ,  Darren Disalvo  2 ,  Hossein Razavi  2 ,  Alan Swinamer  2 ,  Pingrong Liu  2 ,  Qiang Zhang  2 ,  Alison Kukulka  3 ,  Donna Skow  3 ,  Mita Patel  4 ,  Monica Patel  4 ,  Kimberly Fletcher  4 ,  Tara Sherry  4 ,  David Joseph  4 ,  Dustin Smith  4 ,  Melissa Canfield  5 ,  Donald Souza  5 ,  Matthew Bogdanffy  6 ,  Karen Berg  5 ,  Maryanne Brown  5
Affiliations
  • 1. Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: [email protected].
  • 2. Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
  • 3. Compound Profiling Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
  • 4. Drug Discovery Support Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
  • 5. Immunology & Respiratory Disease Research Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
  • 6. Non-Clinical Drug Safety Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA.
PMID: 30595446 DOI: 10.1016/j.bmcl.2018.12.024
Abstract

Exploring various cyclization strategies, using a submicromolar pyrazole HTS screening hit 6 as a starting point, a novel indazole based CCR1 Antagonist core was discovered. This report presents the design and SAR of CCR1 indazole and azaindazole antagonists leading to the identification of three development compounds, including 19e that was advanced to early clinical trials.

Keywords
CCR1; Chemokine receptors; Clinical compound; Indazole; Scaffold hopping.
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