1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists

Andrew M K Pennell; James B Aggen; Subhabrata Sen; Wei Chen; Yuan Xu; Edward Sullivan; Lianfa Li; Kevin Greenman; Trevor Charvat; Derek Hansen; Daniel J Dairaghi; J J Kim Wright; Penglie Zhang

doi:10.1016/j.bmcl.2013.01.005

1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists

Bioorg Med Chem Lett. 2013 Mar 1;23(5):1228-31. doi: 10.1016/j.bmcl.2013.01.005. Epub 2013 Jan 11.

Authors

Andrew M K Pennell¹, James B Aggen, Subhabrata Sen, Wei Chen, Yuan Xu, Edward Sullivan, Lianfa Li, Kevin Greenman, Trevor Charvat, Derek Hansen, Daniel J Dairaghi, J J Kim Wright, Penglie Zhang

Affiliation

¹ ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, CA 94043, USA.

PMID: 23374868
DOI: 10.1016/j.bmcl.2013.01.005

Abstract

A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC(50)=4 nM using [(125)I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species.

MeSH terms

Cell Line
Humans
Piperazines / chemistry
Piperazines / pharmacology*
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, CCR1 / antagonists & inhibitors*
Receptors, CCR1 / metabolism
Structure-Activity Relationship

Substances

CCR1 protein, human
Piperazines
Pyrazoles
Receptors, CCR1