title: Pharmacologic profile of CGS 24128, a potent, long-acting inhibitor of neutral endopeptidase 24.11.
abstract: We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thiorphan and CGS 24128 inhibited NEP in vitro with IC50 values of 5.0 +/- 0.2 and 4.3 +/- 0.2 nM, respectively. After administration at 10 mg/kg intravenously (i.v.), the concentrations of CGS 24128 in the plasma were > 500 nM for 4 h but plasma thiorphan was detectable for only 60 min. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased plasma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 +/- 12% in rats administered exogenous ANP(99-126). This response lasted < 60 min, whereas the same dose of CGS 24128 produced an average increase of 191 +/- 19% in ANPir concentrations that persisted for 4 h. ANP-induced (1 microgram/kg i.v.) natriuresis was significantly potentiated in anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 mg/kg i.v. The change in urinary sodium excretion (UNaV) produced by ANP was 28.8 +/- 4.0 and 15.8 +/- 1.8 muEq/kg/min in CGS 24128- and vehicle-treated rats, respectively. ANP-induced natriuresis was also greater during continuous infusion of thiorphan (5 mg/kg bolus + 0.1 mg/kg/min i.v.; delta UNaV = 29.2 +/- 5.8 and 13.8 +/- 3.2 muEq/kg/min in drug- and vehicle-treated rats, respectively) but not when thiorphan was administered as a bolus (10 mg/kg i.v.) 60 min before the ANP challenge.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
authors.forename: A J
authors.initials: AJ
authors.lastname: Trapani
authors.forename: M E
authors.initials: ME
authors.lastname: Beil
authors.forename: D T
authors.initials: DT
authors.lastname: Coté
authors.forename: S
authors.initials: S
authors.lastname: de Lombaert
authors.forename: M D
authors.initials: MD
authors.lastname: Erion
authors.forename: T E
authors.initials: TE
authors.lastname: Gerlock
authors.forename: R D
authors.initials: RD
authors.lastname: Ghai
authors.forename: M F
authors.initials: MF
authors.lastname: Hopkins
authors.forename: J V
authors.initials: JV
authors.lastname: Peppard
authors.forename: R L
authors.initials: RL
authors.lastname: Webb
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone; D004231:Diuresis / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects; D008297:Male; D008969:Molecular Sequence Data; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D063065:Organophosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015244:Thiorphan / Q000493:pharmacokinetics / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D063065:Organophosphonates; D010446:Peptide Fragments; D015091:beta-Alanine; C087656:CGS 24128; D003900:Desoxycorticosterone; D009320:Atrial Natriuretic Factor; D015244:Thiorphan; D015260:Neprilysin