A Pharmacokinetic and Metabolism Study of the TRPC6 Inhibitor SH045 in Mice by LC-MS/MS

Abstract

TRPC6, the sixth member of the family of canonical transient receptor potential (TRP) channels, contributes to a variety of physiological processes and human pathologies. This study extends the knowledge on the newly developed TRPC6 blocker SH045 with respect to its main target organs beyond the description of plasma kinetics. According to the plasma concentration-time course in mice, SH045 is measurable up to 24 h after administration of 20 mg/kg BW (i.v.) and up to 6 h orally. The short plasma half-life and rather low oral bioavailability are contrasted by its reported high potency. Dosage limits were not worked out, but absence of safety concerns for 20 mg/kg BW supports further dose exploration. The disposition of SH045 is described. In particular, a high extravascular distribution, most prominent in lung, and a considerable renal elimination of SH045 were observed. SH045 is a substrate of CYP3A4 and CYP2A6. Hydroxylated and glucuronidated metabolites were identified under optimized LC-MS/MS conditions. The results guide a reasonable selection of dose and application route of SH045 for target-directed preclinical studies in vivo with one of the rare high potent and subtype-selective TRPC6 inhibitors available.

Transient receptor potential channels’ genes forecast cervical cancer outcomes and illuminate its impact on tumor cells

“…Targeting TRP channels in cervical cancer is shown promising as a therapeutic target. Several TRP channel antagonists and agonists have been developed and tested undergoing preclinical studies testing ( De La Chapa et al, 2019 ; Chai et al, 2022 ; Chen et al, 2023 ; Neuberger et al, 2023 ). However, there is a lack of an evaluation strategy based on the transient receptor potential channels to predict patient prognosis individually.…”