Improved pharmacological chaperones for the treatment of neuronopathic Gaucher and Parkinson's disease

Abstract

Parkinson’s disease (PD) may share an etiological basis with Gaucher disease, as GBA1 mutations lead to Gaucher disease when homozygous, and are associated with increased risk for PD when heteroor homozygous. Neuronopathic forms of Gaucher disease and PD also share the therapeutic challenge of targeting the central nervous system (CNS). Pharmacological chaperones (PC) are orally-available, small molecules that represent an innovative approach to specifically increase the activity of target enzymes. AT2101 is a PC developed to enhance the enzyme deficient in Gaucher disease, glucocerebrosidase (GCase). The accumulation of α-synuclein in the CNS is a hallmark of PD. We have successfully utilized AT2101 for proof-of-concept studies in which administration of AT2101 prevented the accumulation of α-synuclein in the brain of two murine PD models that overexpress human α-synuclein. We reasoned that the CNS exposure and other properties of AT2101 could be further improved while maintaining a good safety profile. For instance, AT2101 inhibits targets other than GCase and has a relatively long lysosomal half-life. An assessment of nearly 200 analogs of AT2101 led to the identification of several new PCs with superior characteristics, including greater CNS penetration, increased potency for enhancement of enzyme activity, accelerated efflux from both tissues and lysosomes, and improved target specificity. These new PCs are currently under investigation in models of Parkinson’s and Neuronopathic Gaucher disease.