Discovery and optimization of pyrazole amides as antagonists of CCR1

  • Bioorg Med Chem Lett. 2019 Feb 1;29(3):435-440. doi: 10.1016/j.bmcl.2018.11.015.
Christian Harcken  1 ,  Christopher Sarko  2 ,  Can Mao  2 ,  John Lord  2 ,  Brian Raudenbush  2 ,  Hossein Razavi  2 ,  Pingrong Liu  2 ,  Alan Swinamer  2 ,  Darren Disalvo  2 ,  Thomas Lee  2 ,  Siqi Lin  3 ,  Alison Kukulka  3 ,  Heather Grbic  4 ,  Mita Patel  4 ,  Monica Patel  4 ,  Kim Fletcher  4 ,  David Joseph  4 ,  Della White  5 ,  Laura Amodeo  5 ,  Karen Berg  5 ,  Maryanne Brown  5 ,  David S Thomson  2
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.
PMID: 30455146 DOI: 10.1016/j.bmcl.2018.11.015
Abstract

A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.

Keywords
CCR1; Chemokine receptors; Development candidate; HTS hit; Pyrazole.
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