Scaffold-based drug discovery

Abstract

The power of the scaffold based lead discovery platform has been demonstrated through the identification and optimization of the pyrazoles as PDE inhibitors. The binding mode of the pyrazole carboxylic ester scaffold does not change when substituents are added. This predictable binding mode anchored by the low-affinity pyrazole carboxylic ester scaffold has greatly increased the efficiency of chemical optimization. All-in-all, a 4000-fold increase in potency was achieved starting from the initial pyrazole carboxylic ester scaffold (IC50 82 μM in PDE4D) to that of the 2-chlorophenyl and 3-nitrophenyl pyrazoles (IC50 20 nM in PDE4D) in two rounds of chemical synthesis and only a total of 21 compounds had to be synthesized. The total molecular weight added is only 121 Daltons, which has resulted in a 4000-fold potency increase. Due to the relatively small size of the compound, additional substitutions can be made to further exploit many available areas of the active site to achieve higher potency and selectivity. There are a number of unique features that differentiate our scaffoldbased lead discovery approach from the fragment-based lead discovery approaches (Erlanson et al., 2004a; Erlanson et al., 2004b; Hartshorn et al., 2005; Nienaber et al., 2000; Rees et al., 2004; Shuker et al., 1996). First, the scaffold library contains compounds that are significantly larger than the basic building blocks with an average molecular weight of about 250D. This has increased the size of the scaffold library to about 20,000 compounds. Furthermore, these scaffold-like compounds contain functional groups that enable them to bind to the protein target at an affinity that could be detected by HTS method. To reduce the high false positive rate associated with lowaffinity biochemical screening, we include other proteins closely related to the target protein (i.e. proteins from the same family) in the screening and only select compounds that show activity against multiple members from the screening panel. Finally, the scaffold validation step ensures that the binding mode is indifferent to substitution. This leads to more predictable SAR and more efficient chemistry in lead optimization. In conclusion, we have developed a strategy that enables rapid and efficient design of novel leads for a given target protein. We have applied our scaffold-based lead discovery platform to rapidly discover the pyrazole carboxylic ester scaffold and to optimize it into potent PDE4 inhibitors. The robustness and efficiency of the scaffold based lead discovery method should make it widely applicable to expedite the lead discovery effort for many other targets for which known small molecule modulators are limited. © 2007 Springer.