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Abstract: FR-PO497

Discovery of a Novel NPT2b Inhibitor That Inhibits Intestinal Phosphate Absorption in Mice and Rats

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Wang, Xiaojun, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Xu, Yanping, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Yu, Xiaohong, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Dey, Asim Bikash, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Zhang, Hong Y., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Zink, Charity, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Wodka, Dariusz, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Porter, Gina, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Matter, William F., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Porras, Leah L., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Reidy, Charles A., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Peterson, Jeffrey A., Eli Lilly and Company, Indianapolis, Indiana, United States
  • Mattioni, Brian, Eli Lilly and Company, Indianapolis, Indiana, United States
  • Wetterau, John, Eli Lilly and Company, Indianapolis, Indiana, United States
Background

Hyperphosphatemia in CKD and ESRD contributes to bone, kidney and CV diseases. Inhibition of the intestinal phosphate (Pi) transporter, NPT2b, may be an approach to augment current therapies for hyperphosphatemia.

Methods

Utilizing radiolabeled Pi uptake assays in CHO cells over-expressing various Pi transporters, and a mouse model, we discovered a novel NPT2b inhibitor, LY3358966. Due to the insoluble nature of the compound at acidic and neutral pH, the sodium salt of the compound was formulated in PVP-VA for further characterization. An amorphous solid dose formulation suitable for clinical development was prepared by spray dry dispersion and incorporated into a capsule and further tested for activity in mice.

Results

LY3358966 inhibited Pi uptake in CHO cells over-expressing human, mouse and rat NPT2b with an IC50 of 32.4, 43.9, and 26.8 nM, respectively. Formulated in PVP-VA and dosed in water, the compound has desirable PK properties for a drug target found on the luminal surface of the small intestine, with low bioavailability, and very low serum free drug concentrations.
LY3358966 acutely (15 min) inhibited Pi absorption in mice with an ED50 of 0.15 mg/kg and Emax of 73%. Four hours after dosing the inhibitor, the ED50 was 1.12 mg/kg and Emax was 79%. In contrast, it acutely inhibited Pi absorption with an ED50 of 0.051 mg/kg and an Emax of only 19% in rats. Importantly, a solid dose formulation of LY3358966 incorporated into a capsule effectively inhibited Pi uptake in mice.
Following three 10 mg/kg doses of LY3358966 and radiolabeled Pi, mouse feces were collected for 48 hours. Compared to placebo treated animals, there was a significant increase in radiolabeled Pi recovered in feces (8.6% of the dose, p < 0.0001).

Conclusion

LY3358966 is a potent NPT2b inhibitor with desirable PK properties that inhibits Pi absorption in mice when dosed in a solid dose formulation acceptable for clinical development. Using a pharmacological approach, we achieved an inhibition of Pi absorption in mice comparable to that reported in NPT2b knockout mouse models. The NPT2b inhibitor had less effect on acute Pi absorption in rats.

Funding

  • Commercial Support