title: Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist.
abstract: (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (1), also known as LY354740, is a highly potent and selective agonist for group II metabotropic glutamate receptors (mGlu receptors 2 and 3) tested in clinical trials. It has been shown to block anxiety in the fear-potentiated startle model. Its relatively low bioavailability in different animal species drove the need for an effective prodrug form that would produce a therapeutic response at lower doses for the treatment of anxiety disorders. We have investigated the increase of intestinal absorption of this compound by targeting the human peptide transporter hPepT1 for active transport of di- and tripeptides derived from 1. We have found that oral administration of an N dipeptide derivative of 1 (12a) in rats shows up to an 8-fold increase in drug absorption and a 300-fold increase in potency in the fear-potentiated startle model in rats when compared with the parent drug 1.
authors.affiliation: Lilly, S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. bueno_ana_belen@lilly.com
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Bueno
authors.forename: Iván
authors.initials: I
authors.lastname: Collado
authors.forename: Alfonso
authors.initials: A
authors.lastname: de Dios
authors.forename: Carmen
authors.initials: C
authors.lastname: Domínguez
authors.forename: José Alfredo
authors.initials: JA
authors.lastname: Martín
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Martín
authors.forename: María Angeles
authors.initials: MA
authors.lastname: Martínez-Grau
authors.forename: Carlos
authors.initials: C
authors.lastname: Montero
authors.forename: Concepción
authors.initials: C
authors.lastname: Pedregal
authors.forename: John
authors.initials: J
authors.lastname: Catlow
authors.forename: D Scott
authors.initials: DS
authors.lastname: Coffey
authors.forename: Michael P
authors.initials: MP
authors.lastname: Clay
authors.forename: Anne H
authors.initials: AH
authors.lastname: Dantzig
authors.forename: Terry
authors.initials: T
authors.lastname: Lindstrom
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Darryle D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stratford
authors.forename: Linda B
authors.initials: LB
authors.lastname: Tabas
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Tizzano
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Wright
authors.forename: Marc F
authors.initials: MF
authors.lastname: Herin
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D000074011:Peptide Transporter 1; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D013216:Reflex, Startle / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism
chemical_list: C503966:2-((2'-amino)propionyl)aminobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D014151:Anti-Anxiety Agents; D001643:Bridged Bicyclo Compounds; D004151:Dipeptides; D000074011:Peptide Transporter 1; D011355:Prodrugs; D018094:Receptors, Metabotropic Glutamate; D027981:Symporters; D000409:Alanine; C104753:eglumetad