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  • From the general synthetic route we first synthesized a dire


    From the general synthetic route, we first synthesized a directed set of analogues of general formula , keeping the synthesis simple by using a symmetrical pyrazole (R=R=Me). The SAR of a set of 30 compounds in the GTPγS binding assay turned out to be quite tight: only 4 (13%) compounds showed moderate activity of <1μM, with a further 6 (20%) compounds between 1 and 5μM. A recent letter by Pfizer of a directed library of pyrazole-4-acetic acids also highlighted a general absence of activity for this substructure. However, this was in ampk pathway to some very potent pyrazoles of similar general structure exemplified by Boehringer Ingelheim. When we investigated further, we saw that there was a clear separation of the tail SAR between the pyrazole series and reported indole-based compounds (). However, in the case of the ortho-sulphonyl benzyl tails (–) the activity was maintained in the pyrazole derivatives and we observed very good potencies. Compound was used as the starting point for further SAR investigations around the tail, and we found a clear preference for the sulfone linker (). The next most active linker after the SO group was the methylene . It is interesting to consider that in these linked bisaryl systems, the conformational preference for both sulfone and methylene is similar, with the two aromatic rings positioned orthogonal to each other. Carbonyl and oxygen linkers are markedly different, favouring conformations in which both aryl rings try to achieve the maximum planarity with respect to the linker group. In accordance, these linkers and respectively lost orders of magnitude of potency with respect to . Hence we reasoned that the position of the terminal aromatic group was important for binding and was generally maintained in subsequent molecules. With the tail linker group fixed as sulfone, we carried out further SAR around the other positions of the tail (). Replacement of the terminal phenyl group with a cycloalkyl group (sulphonamides and ) lost an order of magnitude of potency. More radical changes such as a strongly basic group at the terminus () or a small terminal group () lost even more potency. We also saw that alpha-substitution adjacent to the pyrazole core () showed a dramatic drop in potency. Here the loss was attributed to one (or both) of the following reasons: steric clash of the alpha-methyl group with the pyrazole-5-methyl disrupted the relative conformation between the pyrazole and ring X. Alternatively, the proximity of the alpha-methyl to the sulfone linker was sufficient to disturb the relative conformation between the X and Y rings, a sensitive part of the molecule as we had already observed. Finally replacement of the proximal phenyl ring with a pyrrolidine () lost all activity. Clearly in this series, the SAR was very sensitive to conformational changes of the tail group, with both the rings X and Y preferably aromatic and requiring the correct relative orientation between both themselves and the pyrazole core. With a tight SAR emerging, we profiled compound to evaluate the series (). The first detail that emerged was the almost complete loss of potency in the human whole blood ESC assay. This was followed up with plasma protein binding (PPB) measurements: in human plasma, the true extent of binding was hard to measure and even diluting the plasma to 10% concentration, the extent of binding as measured by equilibrium dialysis was around 99.9%. Protein binding of this order was seen as an issue. While the compound is bound to plasma proteins, it is essentially shielded from the various clearance mechanisms of the body, and an attractive overall PK profile may result. However, the bound compound is also impeded from interacting with the target receptor: large circulating levels of an inactive compound (or very long-lived but very very low free concentrations) lead to little. In terms of physical chemical properties, showed properties expected for a lipophilic carboxylic acid. Permeability and, due to the presence of the carboxylate at physiological pH, solubility were good. At low pH, re-protonation to the carboxylic acid gave a lipophilic, neutral molecule and so solubility dropped away. Both the PPB and PK profile in rat were acceptable and revealed a well absorbed, low clearance compound with a long terminal half-life.