Improved Bioavailability of the mGlu2/3 Receptor Agonist LY354740 Using a Prodrug Strategy: In Vivo Pharmacology of LY544344

Abstract

Numerous studies have indicated that selective agonists of group II metabotropic glutamate (mGlu) receptors, such as LY354740 [(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate] and LY379268 [(Ϫ)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal. Although animal and human studies demonstrate potential therapeutic utility, poor oral bioavailability is a limiting factor in the clinical development of these compounds. Therefore, a novel prodrug approach is being pursued to increase exposure levels of active compound after oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and cerebrospinal fluid levels of LY354740 after oral prodrug administration. Furthermore, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug LY544344 [(1S,2S,5R,6S)-2-[(2ЈS)-(2Ј-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride] in rodent models of psychosis and anxiety. Phencyclidine (PCP)-induced hyperlocomotion was dose dependently inhibited in rats receiving oral administration of 30 or 100 mg/kg LY544344, whereas LY354740 did not significantly reverse PCP-mediated behaviors at doses up to 100 mg/kg. Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound. Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model. The present data confirm that mGlu2/3 receptor agonists produce antipsychotic and anxiolytic effects in animal behavioral models and demonstrate that oral bioavailability of LY354740 was substantially increased using a prodrug strategy.

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

“…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.…”

“…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).…”

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

“…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). However, the doses at which these studies were conducted were relatively low.…”

“…1), emerged from this, based on its active transport and activation profiles. LY544344 has relatively high affinity for hPepT1, is rapidly hydrolyzed in human jejunum and liver homogenates, and displays dramatically improved bioavailability and pharmacologic activity in rodents (Rorick-Kehn et al, 2006). The present experiments were conducted with LY544344 to further elucidate the first-pass activation process and to evaluate dose proportionality in nonclinical species.…”

Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of Agonist (–)-(1R,4S,5S,6S)-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic Acid (LY404039)

“…However, the clinical development of LY354740 has been hampered by low oral bioavailability, due to minimal absorption in the gastrointestinal tract and inadequate penetration through the blood-brain barrier (Johnson et al, 2002;Bueno et al, 2005). Although recent attempts to improve the oral bioavailability of this compound have met with good success (Rorick-Kehn et al, 2006), further research has been devoted to discovering additional potent and selective mGlu2/3 receptor agonists. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of the structurally novel mGlu2/3 receptor agonist (Ϫ)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) (Fig.…”