Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs

Wágner, Gábor; Wéber, Csaba; Nyéki, Olga; Nógrádi, Katalin; Bielik, Attila; Molnár, László; Bobok, Amrita; Horváth, Attila; Kiss, Béla; Kolok, Sándor; Nagy, J; Kurkó, Dalma; Gál, Krisztina; Greiner, István; Szombathelyi, Zsolt; Keserü, György M.; Domány, György

doi:10.1016/j.bmcl.2010.04.075

Cited by 20 publications

(14 citation statements)

References 24 publications

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“…72 These investigations were further inspired by a report by the Gedeon Richter group 73 which disclosed a series of disubstituted oxadiazoles and tetrazoles, including 22À23, as mGlu 5 modulators reminiscent of the Addex based PAMs (Figure 3).…”

Section: Piperidinesmentioning

confidence: 99%

“…Shape-based modeling studies using this now sizable database of compounds within the same scaffold family with propensities for mode switching will be interesting to examine further, with the purpose to hopefully gain a fuller understanding of the molecular Figure 3. Pipiperidinyl cyclobutyl amides and hypotheses for "molecular switch/lock": Addex inspired cyclobutyl amide as "molecular switch" (20), 71 2-piperidinyl oxadiazole HTS NAM lead reported by Gedeon Richter (22), 73 and functionally "inactive" thiophene amide (23). 73 basis for mode switching within these chemotypes.…”

Section: Piperidinesmentioning

confidence: 99%

“…Pipiperidinyl cyclobutyl amides and hypotheses for "molecular switch/lock": Addex inspired cyclobutyl amide as "molecular switch" (20), 71 2-piperidinyl oxadiazole HTS NAM lead reported by Gedeon Richter (22), 73 and functionally "inactive" thiophene amide (23). 73 basis for mode switching within these chemotypes. PAMs containing saturated nitrogen heterocycle ring systems, as first discovered by Addex, continue to show great promise and display a wide range of pharmacological properties.…”

Section: Piperidinesmentioning

confidence: 99%

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Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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ABSTRACT:This Review describes recent trends in the development of small molecule mGlu 5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu 5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu 5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. KEYWORDS:Metabotropic, mGlu 5 , schizophrenia, allosteric, positive allosteric modulator, DFB, CPPHA, CDPPB, ADX-47273, glutamate G lutamate is the single most important excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 The concentration of glutamate within the cytoplasm of glutamatergic neurons is several times more than that of any other amino acid, approximately 5À10 mM, and within synaptic vesicles glutamate reserves can be significantly higher. The two major receptor classes that are known to be modulated by glutamate include ionotropic glutamate receptors (iGlus), which are multimeric glutamate-gated cation channels, and metabotropic glutamate receptors (mGlus), which are seven transmembrane heptahelical (7TM) spanning proteins coupled to effector G-proteins. 2 Ionotropic glutamate receptors are responsible for fast acting glutaminergic transmission in the CNS and are mediated by the three subclasses of iGlus: the R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. All three iGlu channels undergo a conformational change and open in response to glutamate binding and induce excitatory post synaptic current, with the NMDA receptor perhaps best characterized and central to many hypotheses of CNS pathologies. A wide range of neurological disorders including chronic pain, schizophrenia, Alzheimer's disease, epilepsy, drug addiction, and fragile X syndrome have been associated with dysfunction of glutamatergic systems. 1,3 In contrast to ionotropic glutamate receptors, metabotropic glutamate receptors bind glutamate to modulate either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission.Allosteric modulation of metabotropic glutamate receptors as a glutamate-based approach for therapeutic intervention, either via enhancing or inhibiting endogenous agonist responses, is a highly active area of research and drug development. 3À7 Allosteric mechanisms of receptor modulation provide several potential advantages o...

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Section: Piperidinesmentioning

confidence: 99%

Section: Piperidinesmentioning

confidence: 99%

Section: Piperidinesmentioning

confidence: 99%

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Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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“…Structural modification of the hit led to new 1,3-disubstituted oxadiazole (26) and tetrazole with improved binding affinity (2.5-fold and 5-fold, respectively) [53].…”

Section: Anticonvulsant Agentsmentioning

confidence: 99%

“…Among patent compounds, compound 52 displayed inhibitory activity against IDO in low concentrations (< 100 nM) [85]. Some novel 1,2,4-oxadiazole benzoic acid derivatives (53) have been patented by PTC Therapeutics Incorporation as modulators of premature translation termination and/or nonsense-mediated mRNA decay which play a role in a variety of diseases [86][87][88][89].…”

Section: Anticancer Activitymentioning

confidence: 99%

Substituted oxadiazoles: a patent review (2010 – 2012)

Zarghi

Hajimahdi

2013

Expert Opinion on Therapeutic Patents

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Oxadiazoles have been used frequently in drug-like molecules as bioisosteres for ester and amide functionalities and displayed numerous prominent pharmacological effects. The broad pharmacological profile of oxadiazole derivatives has attracted the attention of many researchers to explore this scaffold to its multiple potential against several activities. Therefore, oxadiazole motif is likely to be present in other therapeutic molecules in the future.

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Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

Williams

Jacobson

Kalinichev

et al. 2014

Small Molecule Therapeutics for Schizophrenia

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mGlu 5 receptors have been implicated in the pathophysiology of schizophrenia and cognitive dysfunction, and activation of these receptors has been proposed as a potential therapeutic strategy for treating these diseases. This chapter describes the recent progress in the discovery and development of mGlu 5 positive allosteric modulators (PAMs) as a novel therapeutic approach which does not involve a direct interaction with dopamine receptors. This new class of molecules is structurally very diverse and includes several drug-like chemical series. The pharmacological activity shown by these molecules in preclinical studies confirms their therapeutic potential in all domains of schizophrenia, including positive and negative symptoms and cognitive abnormalities. These data support the development of mGlu 5 PAMs as novel antipsychotic drugs that resonate with the glutamatergic hypofunction hypothesis of schizophrenia. The fine tuning of the functional activity and the clarification of biased signaling pathways in different chemical series may provide clues to achieve efficacy and a good safety profile for novel pharmacotherapies.

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Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs

Cited by 20 publications

References 24 publications

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Substituted oxadiazoles: a patent review (2010 – 2012)

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

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Hit-to-lead optimization of disubstituted oxadiazoles and tetrazoles as mGluR5 NAMs

Cited by 20 publications

References 24 publications

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu5)

Substituted oxadiazoles: a patent review (2010 – 2012)

Activation of the mGlu5 Receptor for the Treatment of Schizophrenia and Cognitive-Deficit-Associated Disorders

Contact Info

Product

Resources

About

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)