Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability

Preclinical Metabolism and Disposition of TP0473292, a Novel Oral Prodrug of the Potent Metabotropic Glutamate 2/3 Receptor Antagonist TP0178894 for the Treatment of Depression

“…Subsequently, we confirmed this assumption by succeeding in the creation of MGS0274 besylate (Urabe et al, 2020;Figure 1C), an l-menthol ester prodrug of an mGlu2/3 receptor agonist MGS0008 which was a glutamate analog and structurally similar to MGS0039 and TP0178894. MGS0274 exhibited a preferable lipophilicity and a higher conversion rate to its active metabolite than MGS0210 in monkey and human liver S9 fractions and achieved a high oral bioavailability (83.7%) as MGS0008 in monkeys with very low plasma exposure to MGS0274 (Kinoshita et al, 2019).…”

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

“…This profile was attributed to poor oral absorption because of low intrinsic membrane permeability due to the high hydrophilicity (log D = −4.02 at pH 6.8) associated with the dual carboxylic moieties and the primary amine (Table 10). 141 It had also been shown that LY404039 ( 2co ), a mGlu2/3R agonist with similar structural features, exhibited poor oral bioavailability of 6% in humans because of low membrane permeability. Ester prodrugs prepared by masking one of the carboxylic acid moieties were examined in an effort to increase intestinal permeability and oral absorption by enhancing drug lipophilicity.…”

Regulation of Glutamatergic Activity via Bidirectional Activation of Two Select Receptors as a Novel Approach in Antipsychotic Drug Discovery

“…Further studies with more homogenous groups of patients and/or without prior medical treatment are needed. Importantly, the poor oral bioavailability of the compounds due to their highly hydrophilic properties was shown to be one of the reasons for their poor efficacy in humans [57,119,120]. One of the solutions to improve the gastrointestinal absorption of compounds is to design prodrugs with better absorption properties.…”

“…An ester-based lipophilic prodrug of another mGlu 2/3 agonist, MGS0008, was designed to avoid undesirable adverse effects [123]. MGS0274 besylate exhibited a 15-fold improvement in oral bioavailability compared to MGS0008, and its administration to patients was accompanied by fewer toxic effects caused by its unnecessary exposure [120,123,124].…”