SAR Analysis Delivers Promising Piezo1 Channel Agonist

Significance

Piezo1 is a mechanosensitive ion channel known to play a crucial role in blood, vascular, and bone development systems. Given its response to mechanical stress dysregulation, Piezo1 is growing as a target for both therapeutic and mechanistic studies. However, probing a mechanosensitive channel with small molecules can be challenging. Deuteration is an alternative route to chemically protect from toxic or unwanted metabolites. Although not incredibly common, there are various phase 1–3 clinical trials and one approved deuterated drug. This work serves as another example of thorough SAR leading to less traditional but more efficacious compounds.

Comment

Yoda1 was discovered through high-throughput screen as a Piezo1 agonist. Its applications are limited to research due to off-target effects stemming from Yoda1’s limited specificity as well as long-term potentiation of Piezo1. Tang et al. maintain the thiadiazole core of Yoda1 and extensively modify both the hydrophobic and hydrophilic moieties to obtain a more active and metabolically stable compound. Ultimately, this resulted in compound A (synthetic steps shown above). A displays improved half-life, clearance, and solubility, as well as a greater than 20-fold increase in agonistic activity on Piezo 1 compared to Yoda1.

Publication History

Article published online:
20 December 2024

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