Abstract 19056: Discovery of Potent and Selective Neprilysin Inhibitors Exhibiting Sustained Pharmacodynamic Activity and Non-renal Elimination in Rats

Introduction: Neprilysin (NEP) inhibitors in combination with angiotensin-II receptor antagonists (ARNIs) have demonstrated benefits in patients with hypertension and chronic heart failure (CHF). A significant population of patients with cardiorenal diseases (e.g., CHF, chronic kidney disease and diabetic nephropathy) exhibit moderate to severe levels of renal impairment. Sacubitril (NEP inhibitor component of LCZ696) is extensively cleared by the kidney and systemic exposures are increased in patients with renal dysfunction thus potentially limiting its therapeutic utility. We aimed to identify potent and selective NEP inhibitors that exhibit non-renal excretion in order to discover agents that may provide optimal therapy in patients with renal dysfunction. Methods: In vitro enzyme activity assays at human NEP were used to assess inhibitory potencies and half-lives of the enzyme-inhibitor complexes. In vivo potentiation of ANP-induced plasma cGMP was evaluated after PO dosing in Sprague Dawley rats. Blood pressure was monitored in conscious Dahl Salt-Sensitive (Dahl/SS) hypertensive rats surgically implanted with telemetry transmitters. Urinary and biliary excretion was evaluated in bile-duct cannulated rats. Results: Selective NEP inhibitors (THRX-213068, THRX-134025, and THRX-124283) were identified with increased potency relative to LBQ657 (active moiety of sacubitril) at NEP (pKi 9.4, 9.3, 9.3 versus 8.2) and displayed longer enzyme residence time (T1/2 = 25, 145, and 190 versus 3 min). All three NEP inhibitors potentiated cGMP to a greater extent than LBQ657 in rat plasma after PO dosing (10 mg/kg). Sustained lowering of mean arterial pressure also was observed in Dahl/SS rats after PO dosing (24 hr average change -17 to -45 mm Hg). Negligible renal excretion was observed for all NEP inhibitors in rats after IV or PO dosing [ Conclusions: Novel, potent, and selective NEP inhibitors were identified that exhibit sustained potentiation of cGMP and BP-lowering in rodent models. Negligible levels of renal excretion were observed in rats suggesting the possibility of providing consistent dosing in patients with cardiorenal diseases across various levels of renal dysfunction.