Selective Dual TRPC3/TRPC6 Inhibitor

A new selective dual TRPC3/TRPC6 small molecule inhibitor GSK2833503A (GSK503A, also denoted as Example 19) ^{25 (link), 26} was provided by GlaxoSmithKline Pharmaceuticals. GSK503A has an IC₅₀ = 21 nM for TRPC3 and 3 nM for TRPC6. Corresponding IC₅₀ for Cav1.2, hERG, Nav1.5, TRPV1, and TRPV4 are 10,000, >50,000, 3300, 6,300, and 12,500 respectively. Cell permeable cGMP-analog (8-pCPT-cGMP) and cAMP-analog (8-Br-cAMP) were obtained from Sigma. For in vivo studies, sildenafil citrate (Revatio, Pfizer) was compressed into soft rodent chow (Transgenic Dough Diet, Bio-Serv) and provided at a dose of 200mg/kg/day for 2 months as described previously ^{27 (link)}. This dose yields a free plasma concentration in the range of 30–50 nM, well within the selective range for PDE5A.

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Seo K., Rainer P.P., Lee D.I., Hao S., Bedja D., Birnbaumer L., Cingolani O.H, & Kass D.A. (2014). Hyperactive Adverse Mechanical-Stress Responses in Dystrophic Heart are Coupled to TRPC6 and Blocked by cGMP-PKG Modulation. Circulation research, 114(5), 823-832.

Publication 2014

8-pCPT-cGMP) 8-Br-cAMP) Transgenic Dough Diet

8 pcpt cgmp Cav1 Cell Cgmp Diet Pde5a Permeable Pharmaceuticals Plasma Revatio Rodent Sildenafil citrate Transgenic Trpc6 Trpv4

Corresponding Organization :

Other organizations : Johns Hopkins University, Medical University of Graz

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Variable analysis

independent variables

GSK2833503A (GSK503A, also denoted as Example 19)

dependent variables

Inhibition of TRPC3 (IC50 = 21 nM)
Inhibition of TRPC6 (IC50 = 3 nM)
Inhibition of Cav1.2 (IC50 = 10,000 nM)
Inhibition of hERG (IC50 > 50,000 nM)
Inhibition of Nav1.5 (IC50 = 3,300 nM)
Inhibition of TRPV1 (IC50 = 6,300 nM)
Inhibition of TRPV4 (IC50 = 12,500 nM)

control variables

Cell permeable cGMP-analog (8-pCPT-cGMP)
CAMP-analog (8-Br-cAMP)
Sildenafil citrate (Revatio, Pfizer) at a dose of 200mg/kg/day for 2 months

positive controls

Sildenafil citrate (Revatio, Pfizer) at a dose of 200mg/kg/day for 2 months

negative controls

Cell permeable cGMP-analog (8-pCPT-cGMP)
CAMP-analog (8-Br-cAMP)

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