Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part II: optimising in vivo clearance

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.2012.09.112

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part II: optimising in vivo clearance

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7707-10. doi: 10.1016/j.bmcl.2012.09.112. Epub 2012 Oct 10.

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. [email protected]

PMID: 23116889
DOI: 10.1016/j.bmcl.2012.09.112

Abstract

The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.

MeSH terms

Animals
Dogs
Drug Discovery*
Hepatocytes / chemistry
Hepatocytes / metabolism
Humans
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
Piperidines
Receptors, CCR3
Receptors, Histamine H1