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.
(+)-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.
Bueno
Ana Belén
AB
Lilly, S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. bueno_ana_belen@lilly.com
Collado
Iván
I
de Dios
Alfonso
A
Domínguez
Carmen
C
Martín
José Alfredo
JA
Martín
Luisa M
LM
Martínez-Grau
María Angeles
MA
Montero
Carlos
C
Pedregal
Concepción
C
Catlow
John
J
Coffey
D Scott
DS
Clay
Michael P
MP
Dantzig
Anne H
AH
Lindstrom
Terry
T
Monn
James A
JA
Jiang
Haiyan
H
Schoepp
Darryle D
DD
Stratford
Robert E
RE
Tabas
Linda B
LB
Tizzano
Joseph P
JP
Wright
Rebecca A
RA
Herin
Marc F
MF
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
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