TY - JOUR
T1 - Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme
AU - Nelissen, J.
AU - Lemkens, P.
AU - Sann, H.
AU - Bindl, M.
AU - Bassissi, F.
AU - Jasserand, D.
AU - De Mey, J. G. R.
AU - Janssen, B. J. A.
PY - 2012/10/15
Y1 - 2012/10/15
N2 - 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 mu M 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 mu mol/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 50 mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 mu mol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 mu mol/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.
AB - 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 mu M 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 mu mol/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 50 mg/kg.day in DOCA-salt hypertensive rats. This treatment lowered BP by 22 mmHg. Steady state concentrations of SOL1 in plasma were 3.9 mu mol/L. In heart, lung, and kidney the concentrations of SOL1 were 0.4, 1.8, and 20.5 mu mol/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.
KW - Endothelin converting enzyme
KW - Neutral endopeptidase
KW - Calcitonin gene-related peptide
KW - Metalloproteases
KW - Kidney
U2 - 10.1016/j.lfs.2012.01.015
DO - 10.1016/j.lfs.2012.01.015
M3 - Article
C2 - 22365954
SN - 0024-3205
VL - 91
SP - 587
EP - 592
JO - Life Sciences
JF - Life Sciences
IS - 13-14
ER -