Structure-activity relationship of N,N′-disubstituted pyrimidinetriones as Ca_V1.3 calcium channel-selective antagonists for Parkinson's disease

Ca_V1.3 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_V1.3 over other LTCC isoforms, especially Ca_V1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a Ca_V1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both Ca_V1.3 and Ca_V1.2 LTCCs. By variation of the substituents on the cyclopentyl and arylalkyl groups of PYT, SAR studies allowed characterization of the Ca_V1.3 and Ca _V1.2 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_V1.3 and Ca_V1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development.