Discovery and optimization of pyrazole amides as antagonists of CCR1

Christian Harcken; Christopher Sarko; Can Mao; John Lord; Brian Raudenbush; Hossein Razavi; Pingrong Liu; Alan Swinamer; Darren Disalvo; Thomas Lee; Siqi Lin; Alison Kukulka; Heather Grbic; Mita Patel; Monica Patel; Kim Fletcher; David Joseph; Della White; Laura Amodeo; Karen Berg; Maryanne Brown; David S Thomson

doi:10.1016/j.bmcl.2018.11.015

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. Epub 2018 Nov 9.

Authors

Christian Harcken¹, Christopher Sarko², Can Mao², John Lord², Brian Raudenbush², Hossein Razavi², Pingrong Liu², Alan Swinamer², Darren Disalvo², Thomas Lee², Siqi Lin³, Alison Kukulka³, Heather Grbic⁴, Mita Patel⁴, Monica Patel⁴, Kim Fletcher⁴, David Joseph⁴, Della White⁵, Laura Amodeo⁵, Karen Berg⁵, Maryanne Brown⁵, David S Thomson²

Affiliations

¹ Medicinal Chemistry Department, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA. Electronic address: christian.harcken@boehringer-ingelheim.com.
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.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, CCR1 / antagonists & inhibitors*
Receptors, CCR1 / metabolism
Structure-Activity Relationship

Substances

Amides
CCR1 protein, human
Pyrazoles
Receptors, CCR1
pyrazole