4-Aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators

Xiong, Hui; Brugel, Todd A.; Balestra, Michael; Brown, Dean G.; Brush, Kelly; Hightower, Caprice; Hinkley, Lindsay; Hoesch, Valerie; Kang, James; Koether, Gerard M.; McCauley, John P.; McLaren, Francis M.; Panko, Laura M.; Simpson, Thomas R.; Smith, Reed W.; Woods, James M.; Brockel, Becky; Chhajlani, Vijay; Gadient, Reto A.; Spear, Nathan; Sygowski, Linda A.; Zhang, Minli; Arora, Jalaj; Breysse, Nathalie; Wilson, Julie M.; Isaac, Methvin; Slassi, Abdelmalik; King, Megan M.

doi:10.1016/j.bmcl.2010.10.036

Cited by 25 publications

(16 citation statements)

References 25 publications

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“…Both compounds also displaced [ 3 H]methoxyPEPy, although this was incomplete over the concentration range tested, likely attributable to low compound affinity. Indeed, another PAM from this same scaffold, the lead compound (2b) (also referred to as CPPZ) with an ∼3-fold higher affinity than DPFE, fully displaced [ Procognitive and Antipsychotic Efficacy of mGlu 5 Modulators (Xiong et al, 2010;Spear et al, 2011). Together these data illustrate that the common mGlu 5 allosteric site can accommodate a diverse array of chemical scaffolds that show not only subtype selectivity but diverse pharmacology.…”

Section: Discussionmentioning

confidence: 94%

“…Several different mGlu 5 PAM chemotypes have been identified, and previous studies have shown that mGlu 5 PAMs from different scaffolds exhibit efficacy in animal models predictive of antipsychotic-like and cognition-enhancing activity (Kinney et al, 2005;Liu et al, 2008b;Spear et al, 2011;Gastambide et al, 2012;Gastambide et al, 2013;Gilmour et al, 2013). Herein, we describe the in vitro and behavioral characterization of two N-aryl piperazine mGlu 5 PAMs: 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289), which was discovered in-house from an evolved high-throughput screening negative allosteric modulator lead , and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE) (disclosed in a patent application by AstraZeneca and NPS [WO 2007/087135;Slassi et al, 2007]), both structural analogs of the recently published mGlu 5 PAM, CPPZ (Spear et al, 2011;Xiong et al, 2010). We found that these N-aryl piperazines were potent cooperativity-driven mGlu 5 PAMs with favorable pharmacokinetic and solubility properties for dosing in vivo and efficacious in preclinical models of NMDAR hypofunction, antipsychotic-like activity, and cognition enhancement.…”

Section: Introductionmentioning

confidence: 99%

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N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Gregory

Herman

Ramsey

et al. 2013

J Pharmacol Exp Ther

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Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-D-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu 5 ) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu 5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca 21 mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu 5 allosteric binding site and high selectivity for mGlu 5 . VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu 5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu 5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Gregory

Herman

Ramsey

et al. 2013

J Pharmacol Exp Ther

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“…The same HTS campaign revealed a NAM that is structurally distinct from the MPEP scaffold and subsequent attempts at optimization of this N -Aryl Piperazine resulted in the identification of a PAM, 2-{4-[2-(benzyloxy)acetyl]piperazin-1-yl}benzonitrile (VU0364289), that also exhibits antipsychotic activity in preclinical models (Zhou et al 2010). A series of 4-aryl piperazine and piperidine amides analogs has also been disclosed as mGlu 5 PAM compounds (Xiong et al 2010) with 1-(4-(2-chloro-4-fluorophenyl) 29 piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone (CPPZ) shown to have activity in two models predictive of antipsychotic activity (Spear et al 2011). Interestingly, the newly disclosed mGlu 5 PAM 4-butoxy-N-(2,4-difluorophenyl)benzamide (VU0357121) has been shown to interact at a structurally distinct site from MPEP and CPPHA but still functionally interacts with the MPEP site(Hammond et al 2010), further illustrating the complexity of interactions that occur within the allosteric binding domain(s).…”

Section: Mglu5 As a Therapeutic Target For Schizophreniamentioning

confidence: 99%

Metabotropic glutamate receptors as therapeutic targets for schizophrenia

Vinson

Conn

2012

Neuropharmacology

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Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking in current therapies for this disorder. Compounds targeting the metabotropic glutamate (mGlu) receptors hold promise as a more comprehensive therapeutic alternative to typical and atypical antipsychotics and may avoid the occurrence of extrapyramidal side effects that accompany these treatments. Activation of the group II mGlu receptors (mGlu2 and mGlu3) and the group I mGlu5 are hypothesized to normalize the disruption of thalamocortical glutamatergic circuitry that results in abnormal glutamaterigic signaling in the prefrontal cortex (PFC). Agonists of mGlu2 and mGlu3 have demonstrated efficacy for the positive symptom group in both animal models and clinical trials with mGlu2 being the subtype most likely responsible for the therapeutic effect. Limitations in the chemical space tolerated by the orthosteric site of the mGlu receptors has led to the pursuit of compounds that potentiate the receptor’s response to glutamate by acting at less highly conserved allosteric sites. Several series of selective positive allosteric modulators (PAMs) for mGlu2 and mGlu5 have demonstrated efficacy in animal models used for the evaluation of antipsychotic agents. In addition, evidence from animal studies indicates that mGlu5 PAMs hold promise for the treatment of cognitive deficits that occur in schizophrenia. Hopefully, further optimization of allosteric modulators of mGlu receptors will yield clinical candidates that will allow full evaluation of the potential efficacy of these compounds in the treatment of multiple symptom domains in schizophrenia patients in the near future.

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“…Shortly thereafter, AstraZeneca released details of their preferred tool compound piperazine CPPZ (83), also containing a benzyloxy acetamide substituent (Figure 11). 94,95 A summary of the pharmacological and DMPK profiles for 82 and 83 described to context of amide replacements, such as thioamide, and several alternate ether oxygen replacements (data not shown), all of which proved deleterious for activity. In addition, it is interesting to note that despite the similar functional potencies for 82 and 83, there is an apparent disconnect in their MPEP site affinities, K i > 30 μM and 2.37 μM, respectively, although it should be noted that both the radioligand and receptor source utilized are slightly different for these MPEP affinity studies.…”

Section: N-aryl Piperazinesmentioning

confidence: 99%

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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4-Aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators

Cited by 25 publications

References 25 publications

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Metabotropic glutamate receptors as therapeutic targets for schizophrenia

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

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4-Aryl piperazine and piperidine amides as novel mGluR5 positive allosteric modulators

Cited by 25 publications

References 25 publications

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

Metabotropic glutamate receptors as therapeutic targets for schizophrenia

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

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