Structure-Optimization and Structure-Activity Relationship of Diphenylpyrazinyl Aminoalkoxyacetic Acid Derivatives: Piperidine Substitution and Hydrophobic Modification as Key Strategies for IP Receptor Agonists

To develop novel, highly potent, and safe IP receptor agonists, two series of diphenylpyrazinyl amino alkoxy acetic acid derivatives were designed and synthesized. Combined with antiplatelet aggregation assays, molecular docking, and molecular dynamics simulations, a systematic investigation was conducted on their structure-activity relationships (SAR). The results revealed that replacing the N -isopropyl group and N -butyl side chain of MRE-269 with a piperidine ring represented the optimal modification strategy, as it enhanced the hydrophobic interactions between the derivatives and the IP receptor while reduce the flexibility of their alkylene chains. The additional introduction of small hydrophobic groups (e.g., methyl and dimethyl groups) onto the alkylene chain could significantly improve the derivatives’ antiaggregatory activity, which represents a key pharmacodynamic feature of this class of compounds. In conclusion, this study clarifies the SAR of these diphenylpyrazinyl amino alkoxy acetic acid derivatives and provides critical insights for the rational design of IP receptor agonists.