Pyrazoloquinazolinecarboxilate analogues inhibit nerve growth factor in vitro

Abstract

NGF is known to regulate the development and survival of select populations of neurons via its binding/activation of the TrkA and p75NTR receptors. However, NGF dysregulation can result in debilitating pathologies. Thus, the identification of small molecules which inhibit NGF signaling have significant therapeutic potential. PD 90780, Ro 08‐2750, and ALE 0540 are small molecules that have been reported to bind and inhibit NGF activity. Importantly, the docking site of these compounds is hypothesized to occur at the loop I/IV cleft of NGF ‐ a region which is required for efficient and selective binding of a neurotrophin to its receptor(s). Molecular modeling predicts these molecules share conserved molecular features and have the ability to bind and modify the molecular topology of NGF. In order to understand the binding mechanism, we synthesized a pyrazoloquinazolinecarboxilate (PQC) analogue series and tested each compound in an NGF‐dependent PC12 cell differentiation assay. In vitro data confirms that the PQC analogues functionally inhibit NGF's agonist effects on PC12 cell differentiation. The results of this study provide evidence to refine the docking mode of PQC‐like compounds for the purposes of inhibiting NGF in vitro. In addition, we identified series analogue PQC 083 which is markedly better than previously described NGF antagonists.