2. Academic Validation
  3. 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

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

  • J Med Chem. 2005 Aug 11;48(16):5305-20. doi: 10.1021/jm050235r.
Ana Belén Bueno 1,  Iván Collado,  Alfonso de Dios,  Carmen Domínguez,  José Alfredo Martín,  Luisa M Martín,  María Angeles Martínez-Grau,  Carlos Montero,  Concepción Pedregal,  John Catlow,  D Scott Coffey,  Michael P Clay,  Anne H Dantzig,  Terry Lindstrom,  James A Monn,  Haiyan Jiang,  Darryle D Schoepp,  Robert E Stratford,  Linda B Tabas,  Joseph P Tizzano,  Rebecca A Wright,  Marc F Herin
Affiliations

Affiliation

  • 1 Lilly, S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. bueno_ana_belen@lilly.com
PMID: 16078848 DOI: 10.1021/jm050235r
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.

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