Daniel Jasserand

Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme

AIMS The pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined. MAIN METHODS The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo. KEY FINDINGS In vitro, at neutral pH, 10 μM SOL1 inhibited NEP-1, NEP-2, and ECE-1 by 99%, 94% and 75%, respectively. The IC(50)s were 25, 25 and 3200 nmol/L, respectively. In anesthetized rats, SOL1 inhibited blood pressure (BP) responses to big-ET-1 and ET-1(1-31) with ED(50)s of 1.9 and 0.03 mg/kg, corresponding to plasma EC(50)s of 4.6 and 0.1 μmol/L, respectively. Pharmacokinetics of SOL1 were examined after single injections in mice and rats. In these species, the estimated clearance of SOL1 varied between 5 and 9 ml/kg.min and T(1/2) between 20 and 60 min. Steady state kinetics of SOL1 were examined after continuous s.c. infusions of SOL1 for 3 weeks at 50mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 μmol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 μmol/kg, respectively. About 63% of the daily dose was retrieved unaltered in the urine. SIGNIFICANCE These data indicate that SOL1 is primarily a NEP inhibitor in vitro as well as in vivo. Given the preferential renal accumulation and renal clearance of SOL1 additional ECE-1 inhibition in the kidney may have contributed to its chronic BP lowering effects in the DOCA-salt hypertensive rat model.

Neutral endopeptidase inhibitors SOL-1 and candoxatril counteract kidney fibrosis by reducing myofibroblast formation in mouse UUO model

Background Interstitial fibrosis is the common pathophysiological mechanism that leads to end organ failure of the both the heart and the kidney. Fibrosis is characterized by an excessive accumulation of myofibroblast-derived extracellular matrix. Peritubular capillary rarefaction precedes renal fibrosis and is secondary to the loss of capillary pericytes to the interstitium. Endothelial-derived C-type natriuretic peptide (CNP) has been demonstrated to have cGMP dependent anti-fibrotic properties most likely due to the interference with pro-fibrotic TGF-b signaling and may counteract the loss of the capillary pericytes. However, natriuretic peptides like CNP are rapidly degraded by neutral endopeptidase (NEP). In a unilateral urether obstruction (UUO) mouse model for kidney fibrosis we assessed the anti-fibrotic effects of Sol-1, a new orally-active compound (Solvay) that inhibits both neutral endopeptidase and endothelin.