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  • Although PGD was initially considered to elicit


    Although PGD was initially considered to elicit its biological actions through a classical PGD receptor (DP1), later findings suggested that several PGD-mediated actions of eosinophils arise via DP2,, which is also known as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). CRTH2 is expressed on inflammatory cells, such as Th2 cells, eosinophils and basophils, and induces the chemotaxis of these cells. CRTH2 also plays important roles in cytokine release by Th2 cells and in the degranulation of eosinophils. CRTH2 antagonists are therefore expected to be useful as anti-inflammatory agents in the treatment of patients with allergic diseases. High throughput screening (HTS) of our chemical library for CRTH2 antagonists identified benzhydryl pyridone compound as a hit (), which inhibited the binding of H-labeled PGD to human and guinea pig CRTH2 receptors on HEK293 cells with IC values of 42 and 256nM, respectively. Moreover, proved to be selective over DP1 (IC>1000nM to human DP1) and displayed oral A-71623 australia in guinea pigs, with oral dosing of at 10mg/kg leading to a maximum plasma concentration () of 0.84μg/mL and area under the blood concentration-time curve (AUC) of 5.95μg·h/mL. In addition, a similar pyridazinone compound was discovered from further HTS. The pyridazinone also showed CRTH2 inhibitory activity and moderate oral absorption, that is, dosing of (10mg/kg) to guinea pigs showed a similar (0.73μg/mL) to and 2.5-fold decrease in AUC (2.40μg·h/mL). Although a number of CRTH2 antagonists have been reported to date, including Ramatroban and indole acetic acids exemplified with compound (), pyridone or pyridazinone scaffolds like or are not known as CRTH2 antagonists and was accordingly selected as a first lead compound. Given that it was discovered by HTS, no information on the structure–activity relationships (SAR) for this compound was available. We therefore attempted to optimize compound in order to obtain SAR and to improve its activity and pharmacokinetic properties. In this paper, we describe our initial optimization efforts and discovery of novel analogs with higher potency for CRTH2. While compound had moderate inhibitory activity against human CRTH2 receptor, its activity against guinea pig CRTH2 was relatively weak at only one-sixth that in humans. The common use of a guinea pig hyperresponsiveness model to examine antiasthmatic activity in vivo mandated that we enhance inhibitory activity against not only human but also guinea pig CRTH2. The synthetic routes to 4,4′-substituted benzhydryl derivatives are shown in . 3-(3-Hydroxypropyl)phenol was alkylated with ethyl bromoacetate in the presence of potassium carbonate in acetonitrile. The resulting alcohol was converted to the corresponding mesylate, followed by displacement with sodium iodide in acetone to afford the alkyl iodide . -Substituted diphenylmethanols were converted to diphenylmethylpyridones in the presence of sulfuric acid at 180–250°C. Pyridones were alkylated with the alkyl iodide in the presence of lithium hydride in ,-dimethylformamide, followed by hydrolysis to give –. The ether-linked compound was synthesized by the routes shown in . A nitrogen atom of pyridone was alkylated with 2-bromoethyl acetate and the resulting acetate was cleaved with sodium hydroxide to afford alcohol . The alcohol was mesylated with methanesulfonyl chloride, followed by alkylation and hydrolysis of the ester to give . The benzamide derivatives – were synthesized as shown in . 3,3-Diphenylpropylamine was alkylated with the iodide to give the secondary amine . Amine was acylated with benzoyl chloride or 4-methoxybenzoyl chloride, followed by hydrolysis of the ester group to afford benzamides –. The synthetic routes to convert the acetic acid moiety are outlined in . 3-(3-Hydroxypropyl)phenol was converted to pyridone in four steps, followed by removal of the benzyl group with trifluoroacetic acid in the presence of 1,2,3,4,5-pentamethylbenzene to give phenol . The hydroxyl group of was alkylated with ethoxycarbonyl bromoalkane, followed by hydrolysis of ethyl ester to afford –. Compound was prepared by similar procedure to that of compound .