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).
Subject(s)
Acetates/pharmacology , Drug Discovery , Indoleacetic Acids/pharmacology , Indoles/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Humans , Indoleacetic Acids/chemistry , Indoles/chemistry , Neutrophils/drug effectsABSTRACT
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.
Subject(s)
Acetates/chemical synthesis , Receptors, Immunologic/agonists , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/agonists , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemistry , Acetates/pharmacology , Animals , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A novel series of zwitterions is reported that contains potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A high quality lead compound 2 was discovered from virtual screening based on the pharmacophore features present in a literature compound 1. Lead optimization through side chain modification and preliminary changes around the acid are disclosed. Optimization of physicochemical properties (log D, MWt, and HBA) allowed maintenance of high CRTh2 potency while achieving low rates of metabolism and minimization of other potential concerns such as hERG channel activity and permeability. A step-change increase in potency was achieved through addition of a single methyl group onto the piperazine ring, which gave high quality compounds suitable for progression into in vivo studies.