Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators

Packiarajan, Mathivanan; Ferreira, Christine G. Mazza; Hong, Sang Phyo; White, Andrew D.; Chandrasena, Gamini; Pu, Xiaosui; Brodbeck, Robbin; Robichaud, Albert J.

doi:10.1016/j.bmcl.2012.08.044

Cited by 14 publications

(7 citation statements)

References 42 publications

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“…16,17 Representatives of major chemotypes are shown in Figure 2 and many of these compounds have demonstrated efficacy in antipsychotic and cognition models. 27–36 In addition, Lilly recently revealed mGlu 5 PAMs LSN2814617 ( 10 ) and LSN2463359 ( 14 ). 28 Both 10 and 14 are reported to shift a concentration-response curve for the group I orthosteric agonist, DHPG, in rat cortical neurons with relatively weak efficacies compared to historical mGlu 5 PAMs ( 10 , FS = 2.8 at 3 µM; 14 , FS = 2.0 at 1 µM).…”

Section: Introductionmentioning

confidence: 99%

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Turlington

Noetzel

Chun³

et al. 2013

J. Med. Chem.

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Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.

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Section: Introductionmentioning

confidence: 99%

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Turlington

Noetzel

Chun³

et al. 2013

J. Med. Chem.

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“…Hubbs et al (2015) has demonstrated that substitution of a morpholine with azetidine disrupted the interactions of morpholine with heme porphyrin ring system, and was successfully applied as a strategy to reduce CYP450 inhibition of the unsubstituted morpholine. Packiarajan et al (2012) have reported a series of azetidinyl oxadiazoles as novel mGluR5 positive allosteric modulators (PAMs) where the azetidine carboxamides due to their low molecular weight (5350) and optimal cLog P (53) showed improved physicochemical and pharmacokinetic properties in comparison to Naryl pyrrolidinonyl oxadiazole leads. Similarly, Zhang et al (2012) have reported the discovery of cyclohexyl azetidinyl functionality as a requisite of potent CCR2 antagonists.…”

Section: Discussionmentioning

confidence: 99%

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

Obach¹,

LaChapelle²,

Brodney

et al. 2016

Xenobiotica

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1.The first generation 5HT-4 partial agonist, 4-{4-[4-Tetrahydrofuran-3-yloxy)-benzo[d]isoxazol-3-yloxymethyl]-piperidin-1-ylmethyl}-tetrahydropyran-4-ol, PF-4995274 (TBPT), was metabolized to N-dealkylated (M1) and an unusual, cyclized oxazolidine (M2) metabolites. M1 and M2 demonstrated pharmacological activity at 5HT receptor subtypes warranting further investigation into their dispositional properties in humans; M2 was a minor component in vitro but was the pre-dominant metabolite identified in human plasma. 2.To shift metabolism away from the piperidine ring of TBPT, a series of heterocyclic replacements were designed, synthesized, and profiled. Groups including azetidines, pyrrolidines, as well as functionalized piperidines were evaluated with the goal of identifying an alternative group that maintained the desired potency, functional activity, and reduced turnover in human hepatocytes. 3.Activities of 4-substituted piperidines or pyrrolidine analogs at the pharmacological target were not significantly altered, but the same metabolic pathways of N-dealkylation and oxazolidine formation were still observed. Altering these to bridged ring systems lowered oxazolidine metabolite formation, but not N-dealkylation. 4.The effort concluded with identification of azetidines as second-generation 5HT partial agonists. These were neither metabolized via N-dealkylation nor converted to cyclized oxazolidine metabolites rather oxidized on the isoxazole ring. The use of azetidine as a replacement for aliphatic aza-heterocyclic rings in drug design to alter drug metabolism and pharmacology is discussed.

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“…Additionally, in rodents, the administration of mGluR 5 NAMs reduced the extent of nigrostriatal toxicity in rodents in response to MPTP [146, 147], 6-OHDA [148, 149], and methamphetamine [150], supporting the use of these drug candidates to exert neuroprotective activity and to slow the progression of neurodegeneration in PD. The relevance of pharmacological blockade of these receptors has inspired the researchers to discover antagonists and NAMs [151-164] targeting mGluR 5 .…”

Section: G-protein-coupled Receptors As Thera-peutic Targets For Parkmentioning

confidence: 99%

In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease

Lemos

Melo

Preto

et al. 2018

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Parkinson's Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel antiparkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenomena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated with dopamine replacement therapy. Being one of the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused on a wide range of therapeutic areas, including Central Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR subclasses, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure- and ligand-based in silico approaches for the development of small molecules to target these receptors.

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Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators

Cited by 14 publications

References 42 publications

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease

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Azetidinyl oxadiazoles as potent mGluR5 positive allosteric modulators

Cited by 14 publications

References 42 publications

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres

In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease

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Product

Resources

About

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)

Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu₅) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)