Published: February 28, 2011 r2011 American Chemical Society 1779 dx.doi.org/10.1021/jm1014549 | J. Med. Chem. 2011, 54, 1779–1788 ARTICLE pubs.acs.org/jmc Zwitterionic CRTh2 Antagonists Tim Luker,* Roger Bonnert, Stuart W. Paine, Jerzy Schmidt, Carol Sargent, Anthony R. Cook, Andrew Cook, Philip Gardiner, Steve Hill, Carol Weyman-Jones, Anil Patel, Stephen Thom, and Philip Thorne Departments of Medicinal Chemistry, DMPK and Discovery BioScience, AstraZeneca R & D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, United Kingdom b S Supporting Information ’ INTRODUCTION Chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTh2) has been identi fied as a G protein- coupled receptor, expressed on human Th2 cells, eosinophils, and basophils. Prostaglandin D 2 (PGD 2 ) is the principal prosta- noid released by immunoglobulin E (IgE)-activated mast cells during asthmatic and allergic reactions. PGD 2 has long been associated with inflammatory conditions and is considered an important mediator in asthma and allergic diseases. 1 The first PGD 2 -specific receptor to be discovered was the DP receptor, 2 but PGD 2 is now also known to be an endogenous agonist of the CRTh2 receptor and promotes chemotaxis of inflammatory cells. 3 Studies have shown that this chemotaxis, as well as that induced by the CRTh2-selective metabolite 13,14-dihydro-15- keto-PGD 2 (DK-PGD 2 ), is blocked by selective CRTh2 antago- nists. Therefore, it is expected that a CRTh2 antagonist would be useful for the treatment of asthma and allergic rhinitis. 4 Ramatroban 5-7 (1, Figure 1), an indole-1-propionic acid, was originally developed as a thromboxane A 2 antagonist for the treatment of thrombosis and coronary artery disease but was later shown to be a relatively potent CRTh2 antagonist. It is possible that the biological efficacy of 1 is at least in part mediated through CRTh2, and the compound has gained approval in Japan for the treatment of allergic rhinitis. Compounds from the AstraZeneca collection with hints of structural similarity to Ramatroban were identified by virtual screening using a speculative pharmacophore consisting of an acidic group connected to an aryl ring by 1-3 atoms. These virtual hits were selected for CRTh2 potency determination to discover novel antagonists. Interestingly, compound 2 was identified (Figure 1), which, despite its very different molecular framework, contained a carboxylic acid and sulfonamide at a broadly comparable spatial arrangement to compound 1. Sur- prisingly, 2 was subsequently found to be a highly potent CRTh2 antagonist (IC 50 = 16 nM). We and others have recently disclosed unrelated CRTh2 antagonists that also contain the phenoxyacetic acid unit. 8 The discovery of 2 was strategically important as it offered the intriguing possibility of delivering a zwitterionic drug candidate (measured base pK a 6.8). This is a novel discovery within the PGD 2 prostanoid area, as the vast majority of candidate drugs are monoacids. The discovery of zwitterion 2 was therefore viewed as an opportunity to deliver substantial changes to absorption-distribution-metabolism- excretion (ADME), selectivity, and toxicity profiles. 9 We now disclose the synthesis and CRTh2 structure-activity relation- ship (SAR) around this new series of zwitterions and how it led to the discovery of exceptionally potent and selective compounds with the superior properties suitable for progression into in vivo toxicology studies. ’ CHEMISTRY The phenoxyacetic acid-derived zwitterions were assembled using the routes highlighted in Scheme 1. Alkylation of 2-hydro- xybenzaldehydes with a bromoacetate ester afforded intermedi- ate 3. This chemistry was tolerant of R-substitution, enabling installation of monomethyl (R 3 = Me) and dimethyl (not shown) groups adjacent to the carboxylic ester. The protected amine side chains were subsequently installed either through reductive amination chemistry or via a reduction/mesylation/alkylation Received: November 11, 2010 ABSTRACT: 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.