title: NESS002ie: a new fluorinated thiol endopeptidase inhibitor with antinociceptive activity in an animal model of persistent pain.
abstract: For the past few decades membrane zinc metallopeptidases have been identified as important therapeutic targets in the control of pain. In particular, neutral endopeptidase (NEP) has been shown to play critical roles in the metabolism of the endogenous peptides Met- and Leu-enkephalins. In this study, we have evaluated the activity of a new fluorinated peptidase inhibitor NESS002ie in both in vitro and in vivo assays. NESS002ie has been compared to the peptidomimetic compound thiorphan and the previously reported NEP selective thiol inhibitor C20. The metallopeptidases inhibitory activity of NESS002ie was tested in vitro using a highly, sensitive, continuous, fluorometric, enzyme assay. Also, the analgesic propriety of NESS002ie, thiorphan and C20 have been evaluated in vivo, by intraplantar, intravenous and intrathecal administration, through nociception assays based on formalin test in mice. Metallopeptidases assays have shown an inhibitory potency of NESS002ie in the nanomolar range for NEP and angiotensin-converting enzyme (ACE). The new fluorinated inhibitor showed higher analgesic activity and bioavailability compared to thiorphan and C20 when administered by both intravenous and intrathecal injections. More significantly, intrathecal injection of NESS002ie reduced both the first and the second phases of the formalin biphasic pain response. In addition, naltrindole and naloxone reversed the analgesic effect of NESS002ie with a diverse profile. This study shows an improvement in relief of inflammation and pain, in vivo, using NESS002ie compared to reference compounds thiorphan and C20. This significant effect could be due to the replacement of isobutyl chain of the thiol C20 with the trifluoromethyl group.
authors.affiliation: Neuroscienze PharmaNess S.c.a.r.l., Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy. Electronic address: simone.tambaro@pharmaness.com.
authors.forename: Simone
authors.initials: S
authors.lastname: Tambaro
authors.forename: Roberta
authors.initials: R
authors.lastname: Reali
authors.forename: Alessandro
authors.initials: A
authors.lastname: Volonterio
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanda
authors.forename: Francesca
authors.initials: F
authors.lastname: Olimpieri
authors.forename: Gérard Aimè
authors.initials: GA
authors.lastname: Pinna
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005557:Formaldehyde / Q000008:administration & dosage; D008297:Male; D051379:Mice; D009270:Naloxone / Q000008:administration & dosage; D010148:Intractable Pain / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013438:Sulfhydryl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000700:Analgesics; C000589445:NESS002ie; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D005557:Formaldehyde; D009270:Naloxone; D014443:Tyrosine
keywords: Angiotensin-converting enzyme; Enkephalinase inhibitor; Formalin test; Inflammatory pain; Neutral endopeptidase; Thiorphan