Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part I

Mark Furber; Lilian Alcaraz; Christopher Luckhurst; Ash Bahl; Haydn Beaton; Keith Bowers; John Collington; Rebecca Denton; David Donald; Elizabeth Kinchin; Cathy MacDonald; Aaron Rigby; Rob Riley; Matt Soars; Brian Springthorpe; Peter Webborn

doi:10.1016/j.bmcl.2012.09.113

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part I

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7702-6. doi: 10.1016/j.bmcl.2012.09.113. Epub 2012 Oct 23.

Authors

Mark Furber¹, Lilian Alcaraz, Christopher Luckhurst, Ash Bahl, Haydn Beaton, Keith Bowers, John Collington, Rebecca Denton, David Donald, Elizabeth Kinchin, Cathy MacDonald, Aaron Rigby, Rob Riley, Matt Soars, Brian Springthorpe, Peter Webborn

Affiliation

¹ AstraZeneca Respiratory & Inflammation iMED, Pepparedsleden 1, 431 83 Mölndal, Sweden. mark1.furber@astrazeneca.com

PMID: 23142617
DOI: 10.1016/j.bmcl.2012.09.113

Abstract

The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.

MeSH terms

Animals
Drug Discovery*
Hepatocytes / chemistry
Hepatocytes / metabolism
Humans
Hydroxamic Acids / chemistry
Hydroxamic Acids / metabolism
Hydroxamic Acids / pharmacology*
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Piperidines / chemistry
Piperidines / metabolism
Piperidines / pharmacology*
Rats
Receptors, CCR3 / antagonists & inhibitors*
Receptors, Histamine H1 / metabolism*
Structure-Activity Relationship
Tissue Distribution

Substances

CCR3 protein, human
Hydroxamic Acids
Piperidines
Receptors, CCR3
Receptors, Histamine H1