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

LIFE SCIENCES

卷:91

Article; Proceedings Paper

Nelissen, J.¹  Lemkens, P.¹  Sann, H.²  Bindl, M.²  Bassissi, F.²  Jasserand, D.²  De Mey, J. G. R.¹  Janssen, B. J. A.¹ 

[1] Maastricht Univ, Dept Pharmacol, Cardiovasc Res Inst Maastricht, NL-6200 MD Maastricht, Netherlands

[2] Abbott Pharmaceut Hannover, Hannover, Germany

关键词: Endothelin converting enzyme;    Neutral endopeptidase;    Calcitonin gene-related peptide;    Metalloproteases;    Kidney;   

DOI  :  10.1016/j.lfs.2012.01.015

来源: Elsevier

【 摘 要 】

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. (c) 2012 Elsevier Inc. All rights reserved.

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