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Aim: To ascertain the quantity and nature of gifts and items provided by the pharmaceutical industry in Australia to medical specialists and to consider whether these are appropriate in terms of justifiable ethical standards, empirical research and views expressed in the literatureDesign and Setting: Fifty-one medical Sydney specialists were asked to collect all gifts, offers, invitations, and items received from pharmaceutical companies in an eight-week period.Main Outcome Measures: The items received were categorised as promotional/educational, drug samples, clinical practice aids, office gifts, personal gifts, and invitations; and were analysed in relation to the pharmaceutical industry Code of Conduct.Results: A large number (mean-42/participant) and wide range of gifts and items were received. These included promotional/educational items (mean= 21), drug samples (mean=8), office gifts (mean=5) and personal gifts (mean-1), clinical aids (mean=3), and invitations (mean=3) to meals, meetings, and conferences. Most gifts and items complied with the Code with a few breaches including offers of entertainment (sporting event and cabaret), items of high monetary value (in competitions with prizes unrelated to medicine), unbranded gifts, and promotional documents presented as journal articles.Conclusions: Medical specialists received many gifts and items from pharmaceutical companies and a few that infringed the Code current at the time of the study. The findings were considered in the light of changes that have since been made to the industry Code of Conduct and professional medical guidelines on ethical relation-ships between physicians and the industry. In large measure, these changes are supported although some suggestions are made for stricter standards. [ABSTRACT FROM AUTHOR]

Incorporating species distributions into conservation planning has traditionally involved long-term representations of habitat use where temporal variation is averaged to reveal habitats that are most suitable across time. Advances in remote sensing and analytical tools have allowed for the integration of dynamic processes into species distribution modeling. Our objective was to develop a spatiotemporal model of breeding habitat use for a federally threatened shorebird (piping plover, Charadrius melodus). Piping plovers are an ideal candidate species for dynamic habitat models because they depend on habitat created and maintained by variable hydrological processes and disturbance. We integrated a 20-year (2000-2019) nesting dataset with volunteer-collected sightings (eBird) using point process modeling. Our analysis incorporated spatiotemporal autocorrelation, differential observation processes within data streams, and dynamic environmental covariates. We evaluated the transferability of this model in space and time and the contribution of the eBird dataset. eBird data provided more complete spatial coverage in our study system than nest monitoring data. Patterns of observed breeding density depended on both dynamic (e.g., surface water levels) and long-term (e.g., proximity to permanent wetland basins) environmental processes. Our study provides a framework for quantifying dynamic spatiotemporal patterns of breeding density. This assessment can be iteratively updated with additional data to improve conservation and management efforts, because reducing temporal variability to average patterns of use may cause a loss in precision for such actions., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

We recently disclosed a set of heteroaryl-fused piperazine inhibitors of BACE1 that combined nanomolar potency with good intrinsic permeability and low Pgp-mediated efflux. Herein we describe further work on two prototypes of this family of inhibitors aimed at modulating their basicity and reducing binding to the human ether-a-go-go-related gene (hERG) channel. This effort has led to the identification of compound 36 , a highly potent (hAβ42 cell IC 50 = 1.3 nM), cardiovascularly safe, and orally bioavailable compound that elicited sustained Aβ 42 reduction in mouse and dog animal models., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5- a ]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC 50 's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC 50 of 1.3 ± 0.39 nM, ∼100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.

We report the development and initial operation of a 6.4 meter perimeter laser gyroscope employing the 543.3 nm, 3s 2 →2p 10 transition of neon. Employing fused silica based supermirrors yielding a cavity Q of 3.9×10 11 and an inferred lock in threshold below 1 μHz, the gyroscope unlocked on the bias provided by Earth rotation alone with a measured Sagnac frequency of approximately 133 Hz, which is 16% larger than that of the 632.8 nm transition.

Global sea-level rise is caused, in part, by more rapid ice discharge from Antarctica, following the removal of the restraining forces of floating ice-shelves after their break-up. A trigger of ice-shelf break-up is thought to be stress variations associated with surface meltwater ponding and drainage, causing flexure and fracture. But until now, there have been no direct measurements of these processes. Here, we present field data from the McMurdo Ice Shelf, Antarctica, showing that the filling, to ~2 m depth, and subsequent draining, by overflow and channel incision, of four surface lakes causes pronounced and immediate ice-shelf flexure over multiple-week timescales. The magnitude of the vertical ice-shelf deflection reaches maxima of ~1 m at the lake centres, declining to zero at distances of <500 m. Our results should be used to guide development of continent-wide ice-sheet models, which currently do not simulate ice-shelf break-up due to meltwater loading and unloading.

In previous studies, the introduction of electron withdrawing groups to 1,4-oxazine BACE1 inhibitors reduced the p K a of the amidine group, resulting in compound 2 that showed excellent in vivo efficacy, lowering Aβ levels in brain and CSF. However, a suboptimal cardiovascular safety margin, based on QTc prolongation, prevented further progression. Further optimization resulted in the replacement of the 2-fluoro substituent by a CF 3 -group, which reduced hERG inhibition. This has led to compound 3, with an improved cardiovascular safety margin and sufficiently safe in GLP toxicity studies to progress into clinical trials.

Background: Patient engagement in research may lead to better-designed studies and improved health outcomes. The objectives of this study were to identify the research priorities of older adults with cancer (OAWCs) and their caregivers and examine how to engage these individuals in research teams and what supports are needed. Methods: We conducted 3 public meetings and 7 focus groups to delineate research priorities and the supports needed to facilitate integration of OAWCs and their caregivers on research teams. Results: A total of 33 older adults and 19 caregivers attended a public meeting and 27 older adults and 17 caregivers participated in a focus group. Most of the OAWCs and their caregivers had never participated in research before. Three themes were identified from the focus groups: (1) motivation to be on a team; (2) ability to make meaningful contributions; and (3) logistical considerations to facilitate engagement. Most participants were motivated to be a research team member and be involved in all steps of research if it could benefit them or future patients and caregivers. OAWCs and their caregivers were highly motivated to improve outcomes. Required logistics included flexibility regarding time and location, accessibility to computer technology, transportation support, materials worded in lay language, and attending/having short training sessions, as well as the presence of peer support. Conclusions: OAWCs and their caregivers are very motivated and willing to participate in research and to be research team members. Logistics and the social aspects of being on a team are important., (Copyright © 2017 by the National Comprehensive Cancer Network.)

The metabotropic glutamate subtype 2 (mGlu 2 ) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu 2 receptor function with a negative allosteric modulator (NAM) enhances activity-dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high-throughput screening (HTS) campaign. The evolution of this hit is described by structure-activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single-digit nanomolar activity in the mGlu 2 NAM GTPγS assay. In addition to SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu 2 receptor occupancy. Finally, to obtain improved drug-like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high in vitro potency., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.

Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This Letter describes the progress and challenges in the continued optimization of the mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212. While many analogs addressed key areas for improvement, no one compound possessed the amalgamation of improvements needed within the (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanone scaffold to advance as a back-up clinical candidate. However, many analogs displayed excellent solubility and physiochemical properties, and were active in the amphetamine-induced hyperlocomotion (AHL) model. Moreover, the SAR was robust for this series of PAMs, and both polar and hydrogen-bond donors were found to be tolerated, leading to analogs with overall attractive profiles and good ligand efficiencies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Herein, we report the structure-activity relationship of a novel series of (2(phenoxymethyl)-6,7-dihydrooxazolo[5,4-c]pyridine-5(4H)-yl(aryl)methanones as potent, selective, and orally bioavailable metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). On the basis of its robust in vitro potency and in vivo efficacy in multiple preclinical models of multiple domains of schizophrenia, coupled with a good DMPK profile and an acceptable therapeutic window, 17a (VU0409551/JNJ-46778212) was selected as a candidate for further development.

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.

We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.

We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE=0.52, LELP=3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.

We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.

This article describes the unique industrial-academic collaboration that has been running for four years between Janssen Pharmaceutica NV and the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) towards identifying the next generation of schizophrenia therapeutics. This was a true collaboration, with both entities engaged in chemistry, In vitro pharmacology, DMPK and In vivo behavioral pharmacology, and aligned to deliver a first-in-class clinical candidate (NME) and additional back-up molecules. Notably, a first NME was delivered in a rapid timeframe and targeted the novel mechanism of mGlu5 positive allosteric modulation. As with any true collaboration, both sides brought unique skills to the table--Janssen leveraged deep drug discovery expertise and infrastructure, while Vanderbilt brought deep knowledge of the chemistry and pharmacology of the target in addition to the ability to provide deep scientific insight into the mechanism behind target modulation. In this article, we will discuss the science which drove our collaboration as well as some key lessons learned.

Allosteric modulation of G protein-coupled receptors has gained considerable attention in the drug discovery arena because it opens avenues to achieve greater selectivity over orthosteric ligands. We recently identified a series of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) for the treatment of schizophrenia that exhibited robust heterotropic activation of CYP3A4 enzymatic activity. The prototypical compound from this series, 5-(4-fluorobenzyl)-2-((3-fluorophenoxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (VU0448187), was found to activate CYP3A4 to >100% of its baseline intrinsic midazolam (MDZ) hydroxylase activity in vitro; activation was CYP3A substrate specific and mGlu(5) PAM dependent. Additional studies revealed the concentration-dependence of CYP3A activation by VU0448187 in multispecies hepatic and intestinal microsomes and hepatocytes, as well as a diminished effect observed in the presence of ketoconazole. Kinetic analyses of the effect of VU0448187 on MDZ metabolism in recombinant P450 or human liver microsomes resulted in a significant increase in V(max) (minimal change in K(m)) and required the presence of cytochrome b5. The atypical kinetics translated in vivo, as rats receiving an intraperitoneal administration of VU0448187 prior to MDZ treatment demonstrated a significant increase in circulating 1- and 4-hydroxy- midazolam (1-OH-MDZ, 4-OH-MDZ) levels compared with rats administered MDZ alone. The discovery of a potent substrate-selective activator of rodent CYP3A with an in vitro to in vivo translation serves to illuminate the impact of increasing intrinsic enzymatic activity of hepatic and extrahepatic CYP3A in rodents, and presents the basis to build models capable of framing the clinical relevance of substrate-dependent heterotropic activation.

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 (mGlu5) 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 mGlu5 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(2+) mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. 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 mGlu5 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 mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia.

Starting from a singleton chromanone high throughput screening (HTS) hit, we describe a focused medicinal chemistry optimization effort leading to the identification of a novel series of phenoxymethyl-dihydrothiazolopyridone derivatives as selective positive allosteric modulators (PAMs) of the metabotropic glutamate 5 (mGlu5) receptor. These dihydrothiazolopyridones potentiate receptor responses in recombinant systems. In vitro and in vivo drug metabolism and pharmacokinetic (DMPK) evaluation allowed us to select compound 16a for its assessment in a preclinical animal screen of possible antipsychotic activity. 16a was able to reverse amphetamine-induced hyperlocomotion in rats in a dose-dependent manner without showing any significant motor impairment or overt neurological side effects at comparable doses. Evolution of our medicinal chemistry program, structure activity, and properties relationships (SAR and SPR) analysis as well as a detailed profile for optimized mGlu5 receptor PAM 16a are described.

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED₅₀ of 5.4 mg/kg sc, indicative of antipsychotic activity.

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topologically similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A cDNA encoding a potassium channel of the two-pore domain family (K(2P), KCNK) of leak channels was cloned from the marine sponge Amphimedon queenslandica. Phylogenetic analysis indicated that AquK(2P) cannot be placed into any of the established functional groups of mammalian K(2P) channels. We used the Xenopus oocyte expression system, a two-electrode voltage clamp and inside-out patch clamp electrophysiology to determine the physiological properties of AquK(2P). In whole cells, non-inactivating, voltage-independent, outwardly rectifying K(+) currents were generated by external application of micromolar concentrations of arachidonic acid (AA; EC(50) ∼30 μmol l(-1)), when applied in an alkaline solution (≥pH 8.0). Prior activation of channels facilitated the pH-regulated, AA-dependent activation of AquK(2P) but external pH changes alone did not activate the channels. Unlike certain mammalian fatty-acid-activated K(2P) channels, the sponge K(2P) channel was not activated by temperature and was insensitive to osmotically induced membrane distortion. In inside-out patch recordings, alkalinization of the internal pH (pK(a) 8.18) activated the AquK(2P) channels independently of AA and also facilitated activation by internally applied AA. The gating of the sponge K(2P) channel suggests that voltage-independent outward rectification and sensitivity to pH and AA are ancient and fundamental properties of animal K(2P) channels. In addition, the membrane potential of some poriferan cells may be dynamically regulated by pH and AA.

Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep-wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.