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

J. Nelissen, P. Lemkens, H. Sann, M. Bindl, F. Bassissi, D. Jasserand, J. G. R. De Mey, B. J. A. Janssen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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/ 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.
Original languageEnglish
Pages (from-to)587-592
JournalLife Sciences
Issue number13-14
Publication statusPublished - 15 Oct 2012


  • Endothelin converting enzyme
  • Neutral endopeptidase
  • Calcitonin gene-related peptide
  • Metalloproteases
  • Kidney


Dive into the research topics of 'Pharmacokinetic and pharmacodynamic properties of SOL1: A novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme'. Together they form a unique fingerprint.

Cite this