Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson’s Disease
Anthony J. Roecker, Kathy M. Schirripa, H. Marie Loughran, Ling Tong, Tao Liang, Kerry L. Fillgrove, Yuhsin Kuo, Kelly Bleasby, Hannah Collier, Michael D. Altman, Melissa C. Ford, Robert E. Drolet, Mali Cosden, Sarah Jinn, Nathan G. Hatcher, Lihang Yao, Monika Kandebo, Joshua D. Vardigan, Rosemarie B. Flick, Xiaomei Liu, Christina Minnick, Laura A. Price, Marla L. Watt, Wei Lemaire, Christine Burlein, Gregory C. Adam, Lauren A. Austin, Jacob Marcus, Sean M. Smith, Mark E. Fraley
Abstract
Parkinson’s disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson’s disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi’s with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.