Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981

Tim Luker; Roger Bonnert; Steve Brough; Anthony R Cook; Mark R Dickinson; Iain Dougall; Chris Logan; Rukhsana T Mohammed; Stuart Paine; Hitesh J Sanganee; Carol Sargent; Jerzy A Schmidt; Simon Teague; Stephen Thom

doi:10.1016/j.bmcl.2011.08.124

Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6288-92. doi: 10.1016/j.bmcl.2011.08.124. Epub 2011 Sep 5.

Authors

Tim Luker¹, Roger Bonnert, Steve Brough, Anthony R Cook, Mark R Dickinson, Iain Dougall, Chris Logan, Rukhsana T Mohammed, Stuart Paine, Hitesh J Sanganee, Carol Sargent, Jerzy A Schmidt, Simon Teague, Stephen Thom

Affiliation

¹ Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, UK. tim.luker@astrazeneca.com

PMID: 21944852
DOI: 10.1016/j.bmcl.2011.08.124

Abstract

Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

MeSH terms

Acetates / chemistry
Acetates / pharmacology*
Drug Discovery*
Humans
Indoleacetic Acids / chemistry
Indoleacetic Acids / pharmacology*
Indoles / chemistry
Indoles / pharmacology*
Neutrophils / drug effects
Receptors, Immunologic / antagonists & inhibitors*
Receptors, Prostaglandin / antagonists & inhibitors*

Substances

Acetates
Indoleacetic Acids
Indoles
Receptors, Immunologic
Receptors, Prostaglandin
AZD1981
prostaglandin D2 receptor