Structure-activity relationship of N,N'-disubstituted pyrimidinetriones as Ca(V)1.3 calcium channel-selective antagonists for Parkinson's disease.

Abstract

CaV1.3 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 CaV1.3 over other LTCC isoforms, especially CaV1.2, is critical to minimize potential side effects. We recently identified pyrimidinetriones (PYTs) as a CaV1.3-selective scaffold; here we report the structure-activity relationship of PYTs with both CaV1.3 and CaV1.2 LTCCs. By variation of the substituents on the cyclopentyl and arylalkyl groups of PYT, SAR studies allowed characterization of the CaV1.3 and CaV1.2 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 CaV1.3 and CaV1.2 LTCCs and highlights several advances in the lead optimization and diversification of this family of compounds for drug development.

• Authors: Soosung Kang, Garry Cooper, Sara Fernandez Dunne, Chi-Hao Luan, D James Surmeier, Richard B Silverman
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 11 Pg. 4786-97 (Jun 13 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23651412 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Calcium Channel Blockers
• Calcium Channels
• Calcium Channels, L-Type
• L-type calcium channel alpha(1C)
• Pyrimidinones
• Cacna1d protein, rat

Topics

• Antiparkinson Agents (chemical synthesis, chemistry, pharmacology)
• Calcium Channel Blockers (chemical synthesis, chemistry, pharmacology)
• Calcium Channels (genetics, metabolism)
• Calcium Channels, L-Type (genetics, metabolism)
• HEK293 Cells
• High-Throughput Screening Assays
• Humans
• Pyrimidinones (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Transfection