title: Pharmacokinetic and pharmacodynamic properties of SOL1: a novel dual inhibitor of neutral endopeptidase and endothelin converting enzyme.
abstract: OBJECTIVE
  The pharmacological profile of the novel putative neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) inhibitor SOL1 was examined.
  
  
  METHODS
  The enzyme inhibitory profile of SOL1 was established in vitro. The pharmacokinetic and pharmacodynamic profile was determined in rodents in vivo.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Nelissen
authors.forename: P
authors.initials: P
authors.lastname: Lemkens
authors.forename: H
authors.initials: H
authors.lastname: Sann
authors.forename: M
authors.initials: M
authors.lastname: Bindl
authors.forename: F
authors.initials: F
authors.lastname: Bassissi
authors.forename: D
authors.initials: D
authors.lastname: Jasserand
authors.forename: J G R
authors.initials: JG
authors.lastname: De Mey
authors.forename: B J A
authors.initials: BJ
authors.lastname: Janssen
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006973:Hypertension / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: C577035:2-((1-(((1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino)carbonyl)cyclopentyl)methyl)-4-((3-(methylamino)propyl)(methyl)amino)-4-oxobutanoic acid; D001552:Benzazepines; D004791:Enzyme Inhibitors; D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; C000606923:ECE1 protein, human; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes