Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Abstract

This review summarizes drug discovery efforts on mGluR2 positive allosteric modulators IntroductionGlutamate is the major excitatory neurotransmitter that plays a role in eliciting and modulating synaptic responses. These processes involve ionotropic (AMPA, NMDA, kainate) and metabotropic receptors. Up to now eight metabotropic glutamate (mGluR) receptors have been described and characterized [1] and were classified into three subgroups based on their similarity in sequence, signaling and pharmacology [2]. Most of the drug discovery interest has been focused to Group I and Group II targets that include mGluR1/mGluR5 and mGluR2/mGluR3 receptors, respectively. Inhibition of mGluR1 receptors has been connected to anxiolytic [3] and analgesic [4] effects. Negative modulation of mGluR5 receptors found to be beneficial in the animal models of anxiety, depression, Fragile-X and autism spectrum disorder (ASD) [5,6]. mGluR5 positive allosteric modulators (PAMs) are believed to be attractive as a potential pharmacotherapy of schizophrenia [7]. In addition to mGluR5 PAMs compounds targeting Group II receptors are also considered as a promising treatment option for schizophrenia. mGluR2 and mGluR3 receptors impact the glutamatergic transmission in certain brain areas implicated in the pathophysiology of schizophrenia. These neurobiological observations have been validated in the experimental models of schizophrenia indicating that Group II mGluR agonists are effective in a number of antipsychotic animal models [8][9][10][11]. One of the best characterized compounds from this class is the mGluR2/3 receptor agonists LY404039 that showed remarkable efficacy in animal

Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information

“…The benzyl substituted benzotriazole derivative 4 was identified from this campaign as an attractive small molecule with low micromolar activity (mGluR2 PAM EC 50 = 3 μM, Figure 2). These data confirmed that 4 is a much smaller (N hev = 16) but still potent compound with higher ligand efficiency (LE = 0.49) as compared to known mGluR2 PAMs 12 (average N hev = 29 ± 4; average LE = 0.25 ± 0.4) that validates it for follow-up studies. Freedom to operate analysis identified only a 5-disubstituted benzotriazole series of Merck 17−19 that was subjected to detailed evaluation.…”

“…Over the past decade a large number of structurally different chemotypes have been disclosed and reviewed . To date, two mGluR2 PAM molecules have reached the clinic (Figure ).…”

“…11 Over the past decade a large number of structurally different chemotypes have been disclosed and reviewed. 12 To date, two mGluR2 PAM molecules have reached the clinic (Figure 1). AZD8529 (2) had been in phase II clinical trial at AstraZeneca in schizophrenic patients; however further development was halted in 2011 due to a lack of efficacy.…”

Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM)

“…The fact that allosteric modulators bind at an alternative site to orthosteric agonists offers multiple potential benefits: opportunity to access a novel chemical space, potential for improved selectivity versus other members of the mGlu family, and lower potential for receptor desensitization and tolerance because PAMs function only in the presence of physiologically controlled levels of glutamate. To date, multiple series of selective mGlu2 receptor PAMs have been described, − and two of them have entered the clinic: 7-methyl-5-[3-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-5-yl]-2-[[4-(trifluoromethoxy)­phenyl]­methyl]-3 H -isoindol-1-one ( 4 , AZD8529) from AstraZeneca and 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1 H )-pyridone ( 5 , JNJ-40411813, also known as ADX71149) from Janssen Pharmaceuticals, Inc. (Janssen) and Addex Therapeutics (Addex). Compound 4 (Figure ) advanced into phase II clinical trials in schizophrenic patients in 2009, but it was discontinued in early 2011 due to lack of efficacy .…”

Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1H-benzimidazol-2-ones as mGlu2 Receptor PAMs

“…A positive allosteric modulator (PAM) can increase the affinity and/or efficacy of the endogenous neurotransmitter glutamate binding to a site topologically distinct from the orthosteric (glutamate) ligand binding sites. PAMs of mGluR 2 have emerged as promising novel therapeutic agents for the treatment of several central nervous system (CNS) disorders. − The mGluR 2 is expressed on presynaptic glutamatergic nerve terminals where it functions as an autoreceptor for glutamate. Thus, a mGlu 2 PAM can normalize excessive glutamatergic neurotransmission, which may be of benefit in disorders such as epilepsy , and schizophrenia. , …”