Structural Modification and Pharmacological Evaluation of (Thiadiazol-2-yl)pyrazines as Novel Piezo1 Agonists for the Intervention of Disuse Osteoporosis

Piezo1 plays a pivotal role in regulating bone remodeling
and homeostasis
and has emerged as a promising target for chemical intervention in
disuse osteoporosis. Nevertheless, the development of small-molecule
Piezo1 agonists is still in its infancy, and highly efficacious Piezo1
agonists are urgently required. In this study, by shedding light on
the structural novelty of the canonical Piezo1 agonist Yoda1, we initiated
a structural optimization campaign based on the (thiadiazol-2-yl)pyrazine
scaffold. A deuterated compound 12a was identified to
be the most potent candidate against Piezo1 with an EC50 value of 2.21 μM, which was over 20-fold more potent than
the reference Yoda1. This compound effectively activated Piezo1 and
initiated Ca2+ influx in MSCs and promoted MSC osteogenesis
via activating the Ca2+-related Erk signaling pathway.
Furthermore, compound 12a was found to alleviate disuse
osteoporosis with a desirable safety profile in a HU (hindlimb-unloading)
rat model, thus warranting it as a potential probe for further investigation.