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

Bueno, Ana B.; Collado, Iván; Dios, Alfonso De; Domı́nguez, Carmen; Martín, José Alfredo; Martı́n, Luisa; Martinez-Grau, Marìa Ángeles; Montero, Carlos Closa; Pedregal, Concepciòn; Catlow, John T.; Coffey, Donald S.; Clay, Michael P.; Dantzig, Anne H.; Lindstrom, Terry D.; Monn, James A.; Jiang, Haiyan; Schoepp, Darryle D.; Stratford, Robert E.; Tabas, Linda B.; Tizzano, Joseph P.; Wright, and Rebecca A.; Hérin, Michel

doi:10.1021/jm050235r

Cited by 59 publications

(41 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There were no reports of convulsions or other neurobehavioral adverse events. Plasma concentrations of LY354740 were comparable to those previously associated with efficacy in GAD (data on file, Eli Lilly and Co.), confirming the utility of using a dipeptide analog to increase the oral bioavailability (by way of peptide transporters) of otherwise poorly absorbed amino-acid analogs such as LY354740 (Bueno et al, 2005;Rorick-Kehn et al, 2006). The use of the prodrug LY544344 is associated with increased oral bioavailability and decreased variability of active moiety (LY354740) in plasma concentration.…”

Section: Ly354740 Plasma Concentrationssupporting

confidence: 68%

“…To improve LY354740 absorption and further assess the therapeutic effects of mGlu2/3 agonists, a pharmacologically inactive peptidyl prodrug (L-alanine) form of the active compound LY354740, named LY544344, was developed. LY544344 is absorbed in the gastrointestinal tract through active PEP T1 transport, with eventual hydrolysis to produce molar equivalents of LY354740 and L-alanine (Bueno et al, 2005;Rorick-Kehn et al, 2006). In rodents, oral administration of LY544344 is associated with at least 10-fold improvement in bioavailability compared with oral LY354740 and behavioral effects comparable to those seen with parenteral administration of LY354740 (Rorick-Kehn et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Dunayevich

Erickson

Levine

et al. 2007

Neuropsychopharmacol

170

View full text Add to dashboard Cite

Section: Ly354740 Plasma Concentrationssupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Dunayevich

Erickson

Levine

et al. 2007

Neuropsychopharmacol

170

View full text Add to dashboard Cite

“…Early in vitro data demonstrated that LY544344 is chemically stable but susceptible to hydrolytic enzymes in jejunal homogenates (Bueno et al, 2005). Previous reports demonstrated that this combination of active absorption and rapid enzymatic hydrolysis results in a dramatic increase in the oral bioavailability of LY354740 in rats (Rorick-Kehn et al, 2006) and humans (Kellner et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…To improve the bioavailability and pharmacokinetic behavior of LY354740, a series of PepT1-targeted peptidyl prodrugs were evaluated using a series of in vitro and in vivo assays (Bueno et al, 2005). An N-linked alanyl prodrug, LY544344 (Fig.…”

mentioning

confidence: 99%

Pharmacokinetics, Metabolism, and Excretion of the Intestinal Peptide Transporter 1 (SLC15A1)-Targeted Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2-Amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in Rats and Dogs: Assessment of First-Pass Bioactivation and Dose Linearity

Perkins¹,

Abraham²

2007

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The peptidyl prodrug (1S,2S,5R,6S)-2-[(2S)-(2-Amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid, also known as LY544344, was discovered to improve the oral bioavailability of the parent drug (؉)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a potent group II metabotropic glutamate receptor agonist. This prodrug has been shown to deliver high plasma concentrations of the active drug via intestinal peptide transporter 1 (SLC15A1) (PepT1)-mediated intestinal transport and presystemic hydrolysis in preclinical species. The current data describe the pharmacokinetic behavior of LY544344 and LY354740, with a specific focus on the first-pass activation processes and dose linearity in rats and dogs. The PepT1 transporter makes an attractive prodrug target because of its high capacity and relatively broad substrate specificity. This was demonstrated by the wide dose proportionality observed in both species (up to 1000 mg/kg in rats and 140 mg/kg in dogs). After oral administration of LY544344, absorption and bioactivation were extensive and rapid, with greater than 97% of prodrug hydrolysis occurring before its appearance in the hepatic portal vein. Systemic activation was likewise extensive, with 100% conversion of a 7-mg/kg intravenous dose in dogs. Radiolabeled studies confirmed that hydrolysis to LY354740 was the only metabolic pathway and that the excretion pattern of the active drug was not altered by administration of the prodrug. These results demonstrate the nearly ideal prodrug properties of LY544344 and further validate the utility of the peptide transporter-directed approach to prodrug design.

show abstract

“…For example, a PET ligand for the mGlu 5 receptor has been developed, allowing a direct comparison of the level of receptor occupancy and distribution of mGlu 5 agonists or antagonists in animals and humans in vivo (Ametamey et al 2006Wyss et al 2007). The development of surrogate efficacy biomarkers has been more challenging, although the effects of the mGlu 2 agonist LY354740 in fear-potentiated startle in both animals and healthy volunteers have been described and can serve as an example for such an approach (Bueno et al 2005;Helton et al 1998;Johnson et al 2003;Tizzano et al 2002;Walker et al 2002). This and mGlu 5 -related PET ligand research will subsequently be described, followed by examples of studies in which direct comparisons are more difficult and a discussion of research in "translatable" paradigms that so far has been conducted in either humans or animals, but not both.…”

Section: Metabotropic Glutamate Receptors In Translationmentioning

confidence: 99%

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

Nordquist

Steckler²,

Wettstein

et al. 2008

Psychopharmacology

View full text Add to dashboard Cite

Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.Results Current data show that animal and human mGlu 5 binding can be directly compared in experiments using the PET ligand 11 C-ABP688. Testing of the mGlu 2/3 receptor agonist LY354740 in the fear-potentiated startle paradigm allows direct functional comparisons between animals and humans. LY354740 has been tested in panic models, but in different models in rats and humans, hindering efforts at translation. Other potentially translatable methods, such as stress-induced hyperthermia and HPA-axis measures, either have been underexploited or are associated with technical difficulties. New techniques such as quantitative trait loci (QTL) analysis may be useful for generating novel biomarkers of anxiety. Conclusions Translational medicine approaches can be valuable to the development of anxiolytics, but the amount of cross-fertilization between clinical and pre-clinical departments will need to be expanded to realize the full potential of these approaches.

show abstract

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

Cited by 59 publications

References 30 publications

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

Pharmacokinetics, Metabolism, and Excretion of the Intestinal Peptide Transporter 1 (SLC15A1)-Targeted Prodrug (1S,2S,5R,6S)-2-[(2′S)-(2-Amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in Rats and Dogs: Assessment of First-Pass Bioactivation and Dose Linearity

Metabotropic glutamate receptor modulation, translational methods, and biomarkers: relationships with anxiety

Contact Info

Product

Resources

About