ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-PO643

Characterization of GFB-8438, a Potent and Selective TRPC5 Inhibitor Under Evaluation for the Treatment of FSGS

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Beconi, Maria, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Ledeboer, Mark, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Yu, Maolin, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Daniels, Matthew, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Malojcic, Goran, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Coeffet-LeGal, Marie F.y, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Pan-Zhou, Xin-Ru, Goldfinch Bio, Cambridge, Massachusetts, United States
  • Mundel, Peter H., Goldfinch Bio, Cambridge, Massachusetts, United States
  • Harmange, Jean-Christophe P., Goldfinch Bio, Cambridge, Massachusetts, United States
Background

The predominant role of podocyte in the development of FSGS is well established. One of the central mechanisms leading to FSGS is the disruption of the podocyte actin cytoskeleton via Rac1 activation. TRPC5 has been identified as a key regulator of Rac1 activation in podocytes and its role was reinforced by the antiproteinuric effect of two TRPC5 small molecule inhibitors in two models of FSGS (Zhou et al, 2017). Here we present the preclinical characterization of GFB-8438, a potent and selective inhibitor of TRPC5. Metabolism, pharmacokinetic and the pharmacology of GFB-8438 will be discussed.

Methods

High throughput screening of a structurally diverse compound collection followed by lead optimization yielded several potent TRPC5 inhibitors. GFB-8438 inhibitory activity against TRPC5 and selectivity across other TRP channels were determined using FLIPR based assays and electrophysiology. Additional profiling was conducted using standard receptor and kinase panels. In vitro routes and clearance mechanisms across species and drug-drug interaction (DDI) potential were evaluated using standard ADME assays. The pharmacokinetic profile was characterized in rats and dogs at 1 mg/kg iv (solution) and at 3, 10, 30 and 100 mg/kg po (suspension). The in vivo efficacy was evaluated in a uni-nephrectomized DOCA-salt rat model of FSGS. PK/PD relationships were derived.

Results

GFB-8438 is a potent TRPC5 inhibitor with high selectivity against TRPC6. Further profiling in standard receptor and kinase panels did not reveal any off-target activities. GFB-8438 is metabolized primarily by oxidation and renal clearance is predicted to be low. Oral bioavailability in rats and dogs is acceptable, with favorable human PK projections given the low rate of hepatic metabolism. When dosed to DOCA-salt rats (single daily dose for 21 consecutive days), GFB-8438 reduced the rate of albuminuria progression without affecting the blood pressure. Rate of albuminuria reduction correlated well with exposure.

Conclusion

GFB-8438 is a potent and selective TPRC5 inhibitor with favorable DMPK and pharmacology characteristics under evaluation for the treatment of FSGS. Characterization in toxicology models is ongoing.

Funding

  • Commercial Support