Structure-Activity Relationship of N,N′-Disubstituted Pyrimidinetriones as CaV1.3 Calcium Channel-Selective Antagonists for Parkinson's Disease

Ca(V)1.3 L-type calcium channels (LTCCs) have been a potential target for Parkinson's disease since calcium ion influx through the channel was implicated in the generation of mitochondrial oxidative stress, causing cell death in the dopaminergic neurons. Selective inhibition of Ca(V)1.3 over other LTCC isoforms, especially Ca(V)1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a Ca(V)1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both Ca(V)1.3 and Ca(V)1.2 LTCCs. By variation of the substituents on the cyclopentyl and arylalkyl groups of PYT, SAR studies allowed characterization of the Ca(V)1.3 and Ca(V)1.2 LTCCs binding sites. The SAR also identified four important moieties that either retain selectivity or enhance binding affinity. Our study represents a significant enhancement of the SAR of PYTs at Ca(V)1.3 and Ca(V)1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development.