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  • br Prostaglandin D PGD is derived from the


    Prostaglandin D (PGD) is derived from the metabolism of arachidonic Q-VD(OMe)-OPh by cyclooxygenases and downstream PGD synthases. In the immune system, PGD is mainly produced by mast cells but also although at lower levels, by macrophages and Th2 lymphocytes. PGD binds to three different receptors, the thromboxane type prostanoid receptor (TP), the PGD receptor (DP, also known as DP1) and the chemoattractant receptor homologous molecule expressed on Th2 lymphocytes (CRTh2, also known as DP2). CRTh2 is a G coupling GPCR, signaling through reduction of intracellular cyclic adenosine monophosphate (cAMP) and calcium mobilization and it is involved in the chemotaxis of Th2 lymphocytes, eosinophils and basophils. CRTh2 also inhibits the apoptosis of Th2 lymphocytes and stimulates the production of IL4, IL5, and IL13, cytokines involved in important biological responses such as eosinophil recruitment and survival, mucus secretion, airway hyper-responsiveness and immunoglobulin E (IgE) production among others. Therefore, molecules that antagonize the pro-inflammatory PGD effects mediated by CRTh2 on key cell types associated with allergic inflammation (basophils, eosinophils and Th2 lymphocytes) should have a potential benefit in related pathologies. Several recent reviews have highlighted the progress and most advanced series of CRTh2 antagonists., Many of the chemical series owe their origins to the observations that the indoleacetic acid indomethacin inhibited the binding of PGD to CRTh2, and that the thromboxane inhibitor, the indolepropionic acid Ramatroban (Baynas®) was also a fairly potent antagonist of CRTh2 (). While robust structural information on the receptor remains elusive, a general preference for an arylacetic acid pharmacophore has emerged. Furthermore, these structures may be conceptually broken into three areas (): We sought to take advantage of known SAR around the indoleacetic acid pharmacophore but applying a conceptual ring expansion of the indole core, revealing a substituted pyrazole (). Two possible ring-openings were considered: this letter addresses our work on pyrazole-4-acetic acids , while the work on pyrazole-1-acetic acids is described elsewhere. A high throughput screening (HTS) campaign of our compound collection revealed compound as a micromolar hit. The methoxypyrazole motif appeared a potential metabolic weak-spot of the molecule so we directly synthesized and characterized dimethyl analogue . Encouragingly, this compound was more active than the original hit in the blockade of radio-labelled [S]-GTPγS binding (). Functional activity was confirmed through the eosinophil shape change assay (ESC) in human whole blood (hWB), showing a modest 10-fold drop in activity, a shift undoubtedly due to binding to plasma proteins. The physicochemical properties were acceptable at this stage for an oral compound so we proceeded to profile the pharmacokinetics in rat. Compound showed low clearance, and good exposure after intravenous dosing. The oral bioavailability was low, but as this was only a hit compound, we were encouraged to continue. The general synthetic route is outlined in . The appropriate diketones were alkylated with -butyl bromoacetate and cyclised with hydrazine to give the pyrazoles . Functionalisation of the pyrazole NH (alkylation, arylation or sulfonylation) followed by acidic deprotection led to the desired pyrazoles . Alternatively, the diketones could be cyclised directly with the appropriate hydrazine to give , followed by acid deprotection. For asymmetrical pyrazoles (R≠R), the step to incorporate the R group inevitably led to the formation of both regioisomers and . According to the conceptual ring opening of , the desired isomer generally required R=aryl and R=methyl. In this case, functionalisation of pyrazoles gave the desired regioisomer as the major product, typically in a ratio of ∼90:10. Direct cyclisation of diketones with aryl hydrazines (R=aryl) also gave regioisomer as the major products. Only in the case of direct cyclisation with alkyl hydrazines (R=alkyl) did the selectivity change, giving the undesired compounds as the major isomer. The separation of the regioisomers and required careful chromatography in each case and the stereochemistry of the products was confirmed by nuclear Overhauser effect (NOE) studies in many cases.