Praliciguat, a Clinical-Stage sGC Stimulator, Improved Glucose Tolerance and Insulin Sensitivity and Lowered Triglycerides in a Mouse Diet-Induced Obesity Model

Abstract

Background: Praliciguat (IW-1973) is a soluble guanylate cyclase (sGC) stimulator in clinical development. In animal models, praliciguat has broad tissue distribution and enhances nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling, which has been shown to elicit hemodynamic, anti-inflammatory, and anti-fibrotic effects. This study assessed the metabolic effects of praliciguat in a mouse DIO model. Methods: Male C57BL/6J mice (12 weeks old at the start of treatment) were either maintained on regular chow (lean mice) or switched to a 60% high fat diet (HFD) starting at age 6 weeks (obese mice). At the start of treatment, obese mice received either praliciguat (6 mg/kg) or vehicle in the HFD. The lean mice remained on regular chow. On day 28, an oral glucose tolerance test (OGTT) was performed after a 3-h fast. On day 29, organs and terminal blood were collected for analysis after a 3-h fast. Results: Praliciguat treatment lowered OGTT glucose area under the curve (-22%, P<0.05), fasting plasma insulin (-53%, P<0.01) and HOMA-IR, an index of insulin resistance (-53%, P<0.01) vs. vehicle treatment. Praliciguat-treated mice also had lower liver (-36%, P<0.05) and fasting circulating triglycerides (-30%, P<0.01) vs. vehicle-treated mice. Furthermore, several fasting biomarkers did not change in treated vs. vehicle including beta-hydroxybutyrate, free fatty acids, plasma glucose, cholesterol, leptin, and adiponectin. Conclusions: Praliciguat improved insulin sensitivity, glucose tolerance, and yielded lower circulating and liver triglycerides in a mouse diet-induced obesity model. Disclosure C.D. Schwartzkopf: None. J. Hadcock: None. J.E. Jones: None. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G.T. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. J. Masferrer: Employee; Self; Ironwood Pharmaceuticals, Inc..