2. Academic Validation
  3. Discovery and optimization of pyrazole amides as antagonists of CCR1

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

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.

Figures
Products