molecules of the month

A furan-containing insurmountable antagonist and inverse agonist of the adenosine A2A receptor for Parkinson’s disease. Kyowa Kirin’s KW-6356, or sipagladenant, is a non-xanthine A2A receptor intended to treat Parkinson’s disease. Unlike Kyowa Kirin’s recently US-approved neutral antagonist, istradefylline, the molecule is an insurmountable antagonist and inverse agonist, both of which may contribute to better efficacy. Unfortunately, despite positive clinical results, the molecule was discontinued for commercial reasons. The molecule is scientifically notable for the GPCR co-crystal structures which provide insight into GPCR insurmountable antagonism and inverse agonism. Antagonism of the A2A receptor is a clinically validated, non-dopaminergic approach to Parkinson’s motor symptom relief. In PD patients, decreased dopamine signaling due to loss of dopaminergic neurons leads to an increase in…