mGlu2 agonist

LY2979165 is a novel potent agent that is used as Anti-depressants. LY2979165 is under clinical study. A Safety Study of LY2979165 is performing in Healthy Subjects. LY2979165 is useful for Anti-depressants.

Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects.[Pubmed:28156011]

Br J Clin Pharmacol. 2017 Aug;83(8):1654-1667.

AIMS: The safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of single and multiple doses of a novel mGlu2 agonist were assessed in healthy males. METHODS: In two, Phase 1 investigator- and subject-blind, placebo-controlled studies, oral doses of prodrug LY2979165 were evaluated: single doses (20-150 mg, N = 30) and multiple once-daily (QD) doses (20-400 mg; N = 84), using a titration regimen. The plasma and urine PK of LY2979165 and active moiety, 2812223, were measured. Cerebrospinal fluid (CSF) was collected to determine PK and neurotransmitter levels. Safety parameters were assessed throughout. RESULTS: Nausea and vomiting were dose limiting following single doses; dose titration allowed higher doses to be tested over 14 days. The most common adverse events related to LY2979165 were dizziness, vomiting, nausea, somnolence and headache. The plasma PK of 2812223 were approximately linear with minimal accumulation with QD dosing. Conversion of LY2979165 to 2812223 was extensive, with minimal LY2979165 measurable in plasma. There was no effect of food on the PK of LY2979165 and 2812223. After 60 mg LY2979165 single-dose, 2812223 exposure in CSF was approximately 2-6% and plasma exposure and peak concentrations were approximately four-fold higher than the mGlu2 agonist in vitro EC50 value. No consistent effects were observed on CSF neurotransmitter levels. CONCLUSIONS: Oral doses of LY2979165 up to 60 mg as a single dose and up to 400 mg given as multiple QD doses, using a titration regimen, were well tolerated with linear PK. Overall, these data support further clinical evaluation of LY2979165.

Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.[Pubmed:26313429]

J Med Chem. 2015 Sep 24;58(18):7526-48.

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2, 6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mGlu2 and mGlu3 amino terminal domain structures.[Pubmed:25602126]

J Med Chem. 2015 Feb 26;58(4):1776-94.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4alpha-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4beta-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Dissociation of mGlu2/3 agonist effects on ketamine-induced regional and event-related oxygen signals.[Pubmed:25943169]

Psychopharmacology (Berl). 2015 Nov;232(21-22):4219-29.

RATIONALE: Validating preclinical biomarkers that predict treatment efficacy remains a critical imperative for neuropsychiatric drug discovery. With the establishment of novel in vivo imaging methods, it has become possible to think how such translational proof-of-concept studies may look. OBJECTIVES: The aim of this study was to use in vivo oxygen (O2) amperometry to simultaneously assess the regional and event/task-related O2 changes induced by ketamine challenge in rats, and to determine whether both of these signals are equivalently affected by the mGlu2/3 receptor agonist LY379268. METHODS: O2 signals were measured via carbon paste electrodes implanted in the anterior cingulate cortex (ACC) of rats trained to perform a simple reaction time task (SRT). SRT performance, event-related ACC O2 responses, and regional ACC O2 signal were recorded simultaneously in animals treated with ketamine (10 mg/kg) and/or LY379268 (3 mg/kg). RESULTS: A consistent relationship was observed between baseline SRT performance and related ACC O2 signals, suggesting that ACC engagement is likely to be a requirement for optimal task performance. Ketamine induced a robust and consistent slowing in reaction times that was reflected by a delayed event-related ACC O2 signal increase compared to vehicle controls. Ketamine also produced a regional and task-independent 60-min increase in ACC O2 levels which was effectively attenuated by LY379268. However, LY379238 failed to reverse alterations in event-related O2 signals and associated SRT task performance. CONCLUSIONS: These findings raise questions about the degree to which such reversals of regional ketamine O2 signals could potentially be claimed to predict drug treatment efficacy.