Discovery of Oxazolobenzimidazoles as Positive Allosteric Modulators for the mGluR2 Receptor

Garbaccio, R. M.; Brnardic, Edward J.; Fraley, Mark E.; Hartman, George D.; Hutson, Pete H.; O’Brien, Julie A.; Magliaro, Brian C.; Uslaner, Jason M.; Huszar, Sarah L.; Fillgrove, Kerry L.; Small, James H.; Tang, Cuyue; Kuo, Yuhsin; Jacobson, Marlene A.

doi:10.1021/ml100115a

Cited by 25 publications

(19 citation statements)

References 26 publications

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“…Compound 42 is a representative from this invention with an EC 50 value of 11 nM. Detailed SAR and pharmacological investigation of oxazolobenzimidazoles are described in a separate publication [90]. Optimization of the oxazolidinone through physical and pharmacokinetic properties led to the identification of potent and orally bioavailable compounds, such as compound 43, also known as TBPCOB.…”

Section: Oxazolobenzimidazolesmentioning

confidence: 99%

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Szabó¹,

Keserü²

2014

CTMC

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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

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Section: Oxazolobenzimidazolesmentioning

confidence: 99%

Positive Allosteric Modulators for mGluR2 Receptors: A Medicinal Chemistry Perspective

Szabó¹,

Keserü²

2014

CTMC

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“…This cyclization locks a co-planar conformation which is suggested to be preferred for mGlu2 receptor PAM activity (Fig. 25) [124]. From the data presented in Merck's patent application, it can be deduced that aryloxymethyl-or heretoaryloxymethyl-groups are largely preferred as substituents at C 2 , with the absolute (S)-configuration at the C 2 stereogenic centre in most cases.…”

Section: Oxazolobenzimidazolesmentioning

confidence: 92%

“…26). An attempt to introduce some polarity and partial basicity in this area of the molecules resulted in the preparation of a subset of pyridyl analogues [124]. The most interesting compound, TBPCOB (68, Fig.…”

Section: Oxazolobenzimidazolesmentioning

confidence: 99%

Metabotropic Glutamate Receptor 2 Activators

Cid¹,

Trabanco²,

Lavreysen

2014

Small Molecule Therapeutics for Schizophrenia

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Schizophrenia is a common and severe, often disabling psychiatric illness of unknown aetiology that affects approximately 24 million people worldwide. The illness is characterized by symptomatology comprising positive symptoms (hallucinations and delusional behaviours), negative symptoms (anhedonia, social withdrawal and apathy) and cognitive dysfunction (diminished capacity for learning, memory and executive function). Current pharmacological treatments are effective at alleviating positive symptoms but have limited impact on negative symptoms and cognitive deficits. Furthermore, the extrapyramidal symptoms, hyperprolactinemia and metabolic syndrome, including substantial weight gain, are typical side effects limiting the value of many of these drugs for patients. Thus, drugs that better serve the patient population by effectively treating all symptoms with improved safety and tolerability remain a critical unmet need. Modulation of the metabotropic glutamate type 2 (mGlu2) receptor has emerged as a promising mechanism for the treatment of CNS diseases, with the potential to provide a new and more effective avenue for the treatment of schizophrenia.

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“…Figure 8 shows the compounds that were reported to have an EC 50 value of less than 30 nM. They are N-aryl-N-(pyridylmethyl)ethanesulfonamides (76) (Barda et al, 2004;Johnson et al, 2003), biphenyl-indanones (77) , 1,4-disubstituted 3-cyanopyridone derivatives (78) (Imogai et al, 2007), 3-(Imidazolyl methyl)-3-azabicyclo[3.1.0]hexan-6-yl)methyl ethers (79 and 80) , oxazolobenzimidazoles (81) (Garbaccio et al, 2010), 3-Benzyl-1,3-oxazolidin-2-ones (82 and 83) (Duplantier et al, 2009), 2-((4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-5,6-dihydro-4H-imidazo[4,5,1-ij][1,7]naphthyridine (84) and THIIC (85) (Fell et al, 2011). Woltering et al, 2008a;Woltering et al, 2008b;Woltering et al, 2010), imidazole derivatives (88) (Gatti McArthur et al, 2006b), pyrazolopyrimidines (89) (Gatti McArthur et al, 2006c), Pyridine and pyrimidine derivatives (90 and 91) (Gatti Mcarthur et al, 2007), acetylenyl-pyrazolo-pyrimidine derivatives (92 and 93) (Gatti McArthur et al, 2006a).…”

Section: Allosteric Modulators For Mglur2mentioning

confidence: 99%