Unveiling a Potent TRPC Channel Inhibitor: Pharmacological Insights and Therapeutic Potential

The transient receptor potential canonical 6 (TRPC6) has been linked with various diseases such as focal segmental glomerulosclerosis, pulmonary hypertension, and lung edema caused by ischemia-reperfusion. A quest was initiated to identify new TRPC6 channel inhibitors and to explore their therapeutic efficacy.

A collection of TRPC channel inhibitors was crafted and synthesized. The potency of these compounds was evaluated by monitoring the levels of intracellular calcium (Ca2+). The leading compound, SAR7334, was scrutinized further using whole-cell patch-clamp methods. The impact of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic blood pressure (BP) was also examined.

SAR7334 was found to inhibit the Ca^2+ influx into cells mediated by TRPC6, TRPC3, and TRPC7 with IC50 values of 9.5, 282, and 226 nM, respectively. However, TRPC4 and TRPC5-mediated calcium entry remained unaffected. Patch-clamp studies validated that the compound obstructed TRPC6 currents with an IC50 of 7.9 nM. Additionally, SAR7334 curtailed TRPC6-driven acute HPV in isolated perfused lungs from mice. Pharmacokinetic evaluations revealed that SAR7334 was appropriate for long-term oral administration. In a preliminary short-term study, SAR7334 did not alter the mean arterial pressure in spontaneously hypertensive rats (SHR).

The findings underscore the role of TRPC6 channels in hypoxic pulmonary vasoregulation and suggest that these channels are not significantly involved in BP regulation in SHR. SAR7334, a novel and highly potent inhibitor of TRPC6 channels with good bioavailability, presents new avenues for studying TRPC channel function in vivo.