Switching between agonists and antagonists at CRTh2 in a series of highly potent and selective biaryl phenoxyacetic acids

Tim Luker; Roger Bonnert; Jerzy Schmidt; Carol Sargent; Stuart W Paine; Stephen Thom; Gary Pairaudeau; Anil Patel; Rukhsana Mohammed; Elizabeth Akam; Iain Dougall; Andrew M Davis; Phil Abbott; Steve Brough; Ian Millichip; Thomas McInally

doi:10.1016/j.bmcl.2011.04.101

Switching between agonists and antagonists at CRTh2 in a series of highly potent and selective biaryl phenoxyacetic acids

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3616-21. doi: 10.1016/j.bmcl.2011.04.101. Epub 2011 Apr 28.

Authors

Tim Luker¹, Roger Bonnert, Jerzy Schmidt, Carol Sargent, Stuart W Paine, Stephen Thom, Gary Pairaudeau, Anil Patel, Rukhsana Mohammed, Elizabeth Akam, Iain Dougall, Andrew M Davis, Phil Abbott, Steve Brough, Ian Millichip, Thomas McInally

Affiliation

¹ Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, UK. [email protected]

PMID: 21592791
DOI: 10.1016/j.bmcl.2011.04.101

Abstract

A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.

MeSH terms

Acetates / chemical synthesis*
Acetates / chemistry
Acetates / pharmacology
Animals
Humans
Inhibitory Concentration 50
Molecular Structure
Rats
Receptors, Immunologic / agonists*
Receptors, Immunologic / antagonists & inhibitors*
Receptors, Prostaglandin / agonists*
Receptors, Prostaglandin / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Acetates
Receptors, Immunologic
Receptors, Prostaglandin
prostaglandin D2 receptor
phenoxyacetic acid