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1.  Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2. Development of a [3.3.0]-based series and other piperidine bioisosteres 
This letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.
doi:10.1016/j.bmcl.2014.01.011
PMCID: PMC3951244  PMID: 24462664
GlyT1; Scaffold hopping; transporter; schizophrenia
2.  Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1. Development of a potent and CNS penetrant [3.1.0]-based lead 
This letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition).
doi:10.1016/j.bmcl.2014.01.013
PMCID: PMC3951249  PMID: 24461352
GlyT1; Scaffold hopping; transporter; schizophrenia
3.  Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety 
Bioorganic & medicinal chemistry letters  2013;23(21):10.1016/j.bmcl.2013.09.001.
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.
doi:10.1016/j.bmcl.2013.09.001
PMCID: PMC3846293  PMID: 24074843
4.  Dihydrothiazolopyridone Derivatives as a Novel Family of Positive Allosteric Modulators of the Metabotropic Glutamate 5 (mGlu5) Receptor 
Journal of medicinal chemistry  2013;56(18):7243-7259.
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.
doi:10.1021/jm400650w
PMCID: PMC3924858  PMID: 23947773
5.  Substituted 1-Phenyl-3-(pyridin-2-yl)urea Negative Allosteric Modulators of mGlu5: Discovery of a New Tool Compound VU0463841 with Activity in Rat Models of Cocaine Addiction 
ACS Chemical Neuroscience  2013;4(8):1217-1228.
Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu5 negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu5 NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound 29 (VU0463841) with good CNS exposure in rats. The utility of 29 (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction.
doi:10.1021/cn400070k
PMCID: PMC3750677  PMID: 23682684
mGlu5; negative allosteric modulator; noncompetitive antagonist; CNS; cocaine; addiction
6.  Impact of Isoflurane Anesthesia on D2 Receptor Occupancy by [18F]fallypride Measured by MicroPET With a Modified Logan Plot 
Synapse (New York, N.Y.)  2011;65(11):1173-1180.
In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [18F]fallypride administration to estimate the distribution volume ratio DVR′ (DVR′ ∝ DVR; DVR = 1 + BPND, where BPND is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [18F]fallypride DVR′.
Methods
Rats were injected with [18F]fallypride either unconsciously under ~1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [18F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [18F]fallypride i.v. while under 1.5% isoflurane. The DVR′ estimates from the 60 min acquisitions were compared with the DVR′ from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time–activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k3/k4 (≈ BPND) for the 60 and 120 min acquisitions.
Results
Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR′ estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ~30% reduction in k3/k4 for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer).
Conclusion
The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [18F]fallypride BPND in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors.
doi:10.1002/syn.20955
PMCID: PMC4078917  PMID: 21584868
[18F]fallypride; dopamine (DA) receptors; isoflurane; graphical analysis; microPET
7.  Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity 
Biological psychiatry  2012;73(6):501-509.
Background
Metabotropic glutamate receptor subtype 5 (mGlu5) activators have emerged as a novel approach to the treatment of schizophrenia. Positive allosteric modulators (PAMs) of mGlu5 have generated tremendous excitement and fueled major drug discovery efforts. Although mGlu5 PAMs have robust efficacy in preclinical models of schizophrenia, preliminary reports suggest that these compounds may induce seizure activity. Prototypical mGlu5 PAMs do not activate mGlu5 directly but selectively potentiate activation of mGlu5 by glutamate. This mechanism may be critical to maintaining normal activity-dependence of mGlu5 activation and achieving optimal in vivo effects.
Methods
Using specially engineered mGlu5 cell lines incorporating point mutations within the allosteric and orthosteric binding sites, as well as brain slice electrophysiology and in vivo electroencephalography and behavioral pharmacology, we found that some mGlu5 PAMs have intrinsic allosteric agonist activity in the absence of glutamate.
Results
Both in vitro mutagenesis and in vivo pharmacology studies demonstrate that VU0422465 is an agonist PAM that induces epileptiform activity and behavioral convulsions in rodents. In contrast, VU0361747, an mGlu5 PAMs optimized to eliminate allosteric agonist activity, has robust in vivo efficacy and does not induce adverse effects at doses that yield high brain concentrations.
Conclusions
Loss of the absolute dependence of mGlu5 PAMs on glutamate release for their activity can lead to severe adverse effects. The finding that closely related mGlu5 PAMs can differ in their intrinsic agonist activity provides critical new insights that is essential for advancing these molecules through clinical development for treatment of schizophrenia.
doi:10.1016/j.biopsych.2012.09.012
PMCID: PMC3572342  PMID: 23140665
Glutamate; allosteric modulators; agonist; schizophrenia; seizure; convulsions; mGlu5
8.  The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson’s disease 
Neuropharmacology  2012;66:187-195.
Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson’s disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu8-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (two hour) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18–20 hours) or reserpine (18–20 hours), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 hour pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu8 may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D2-like dopamine receptors is prolonged and indicate that selective activation of mGlu8 may represent a novel therapeutic strategy for alleviating the motor symptoms of PD.
doi:10.1016/j.neuropharm.2012.03.029
PMCID: PMC3432150  PMID: 22546615
9.  Discovery of a selective M4 positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia 
Herein we report a next generation muscarinic receptor 4 (M4) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC50 = 56 nM) and rat (EC50 = 176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (Fold Shift, human = 106; rat = 50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.
doi:10.1016/j.bmcl.2012.10.073
PMCID: PMC3535830  PMID: 23177787
Muscarinic receptor 4; Positive allosteric modulator; Amphetamine induced hyperlocomotion; CNS; PAM
10.  Discovery of the First Highly M5-Preferring Muscarinic Acetylcholine Receptor Ligand, an M5 Positive Allosteric Modulator Derived from a Series of 5-Trifluoromethoxy N-Benzyl Isatins 
Journal of medicinal chemistry  2009;52(11):10.1021/jm900286j.
This report describes the discovery and initial characterization of the first positive allosteric modulator of muscarinic acetylcholine receptor subtype 5 (mAChR5 or M5). Functional HTS, identified VU0119498, which displayed micromolar potencies for potentiation of acetylcholine at M1, M3, and M5 receptors in cell-based Ca2+ mobilization assays. Subsequent optimization led to the discovery of VU0238429, which possessed an EC50 of approximately 1.16 µM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity.
doi:10.1021/jm900286j
PMCID: PMC3875304  PMID: 19438238
11.  Discovery and SAR of a novel series of non-MPEP site mGlu5 PAMs based on an aryl glycine sulfonamide scaffold 
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu5 PAM chemotype.
doi:10.1016/j.bmcl.2012.10.068
PMCID: PMC3539767  PMID: 23142615
metabotropic glutamate receptor 5; mGlu5; positive allosteric modulator (PAM); non-MPEP
12.  Emerging Approaches for Treatment of Schizophrenia: Modulation of Cholinergic Signaling 
Discovery medicine  2012;14(79):413-420.
Currently available therapeutic agents for treatment of schizophrenia target signaling by monoaminergic neurotransmitters; however, these treatments do not adequately treat the range of symptoms observed in patients. While these therapies treat the positive symptoms, they do not have efficacy in treating the negative symptoms and cognitive deficits that are associated with the disease. Evidence suggests that molecules that modulate signaling by the neurotransmitter acetylcholine (ACh) could provide a more comprehensive treatment of schizophrenia than currently prescribed antipsychotics. Molecules that broadly increase ACh-signaling have been demonstrated to have efficacy in treating numerous symptom clusters in schizophrenia patients. Unfortunately, these compounds induce adverse effects via activation of peripheral receptors that limit their clinical utility. One proposed strategy for retaining the efficacy of cholinergic treatments, without the adverse effects, is to target specific cholinergic receptor subtypes in the brain. Several cholinergic receptors are able to modulate brain circuits that are dysregulated in schizophrenia patients including receptors belonging to both the muscarinic family (i.e., M1, M4, and M5), and the nicotinic family (i.e., α7, α4β2). Recently, great strides have been made in developing small molecules with high specificity for these receptors, and several of these novel molecules have robust efficacy in several preclinical models predictive of both anti-psychotic and pro-cognitive effectiveness. Promising studies suggest that targeting M1 and α7 may be beneficial for pro-cognitive effects, while molecules that target M4 may be ideally suited to address the positive symptoms. Since these receptor subtypes are distinct from those responsible for the adverse effects observed with non-selective cholinergic treatments, there is hope that molecules targeting these receptors could provide novel therapeutics. Further research is needed to examine the utility of such compounds as therapeutics that could be used either alone, or in combination with existing medications, to better treat schizophrenia.
PMCID: PMC3726271  PMID: 23272693
13.  Optimization of an ether series of mGlu5 positive allosteric modulators: Molecular determinants of MPEP-site interaction crossover 
We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) 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.
doi:10.1016/j.bmcl.2012.08.043
PMCID: PMC3755010  PMID: 22981332
Metabotropic glutamate receptor 5; mGlu5; Positive allosteric modulator (PAM); Non-MPEP
14.  Emerging Approaches for Treatment of Schizophrenia: Modulation of Glutamatergic Signaling 
Discovery medicine  2012;14(78):335-343.
Treatment options for schizophrenia that address all symptom categories (positive, negative, and cognitive) are lacking. Novel compounds that regulate signaling by the major excitatory neurotransmitter in the brain, glutamate, are emerging as a novel approach for the treatment of this disorder. Currently available medications ameliorate positive symptoms but do not have efficacy in reducing negative symptoms or cognitive disturbances. It is possible that agents that target glutamatergic signaling in the CNS could have efficacy in reducing all major symptom clusters, providing a more comprehensive treatment strategy, and also avoiding some of the adverse effects that are seen with currently available treatments. Three major approaches for targeting glutamate signaling are now advancing in preclinical and clinical development. First are inhibitors for a transporter for glycine termed GlyT1. Glycine is a co-agonist with glutamate for a specific subtype of glutamate receptor, termed the NMDA receptor, which is thought to be critically involved in brain circuits that are disrupted in schizophrenia patients. Inhibiting GlyT1 increases glycine levels and can selectively increase NMDA receptor signaling. Another promising approach is to increase activity of another family of glutamate receptors, termed metabotropic glutamate receptors (mGlus), which play important modulatory roles in brain circuits that are thought to be disrupted in schizophrenia patients. Activation of the group I (mGlu5) and the group II (mGlu2 and mGlu3) mGlus is hypothesized to normalize the disruption of aberrant signaling in these circuits. Novel drug-like molecules that increase activity of these receptors have robust efficacy in animal models that predict efficacy in treatment of schizophrenia. Early clinical studies provide some support for potential utility of these targets in reducing symptoms in schizophrenia patients. Clinical studies that are underway will provide further insights into the potential utility of these compounds in the treatment of multiple symptom domains in schizophrenia patients.
PMCID: PMC3787874  PMID: 23200065
15.  Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor 
Herein we describe the discovery and development of a novel class of M4 positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC50 = 1.3 µM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration-response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 µM, B:P = 0.85).
doi:10.1016/j.bmcl.2012.05.109
PMCID: PMC3401285  PMID: 22738637
Positive allosteric modulator; M4; ML293; CNS penetration; Muscarinic receptor 4
17.  Development of a more highly selective M1 antagonist from the continued optimization of the MLPCN Probe ML012 
This Letter describes the continued optimization of an MLPCN probe molecule (ML012) through an iterative parallel synthesis approach. After exploring extensive modifications throughout the parent structure, we arrived at a more highly M1-selective antagonist, compound 13l (VU0415248). Muscarinic subtype selectivity across all five human and rat receptors for 13l, along with rat selectivity for the lead compound (ML012), is presented.
doi:10.1016/j.bmcl.2011.11.110
PMCID: PMC3434972  PMID: 22197142
Muscarinic acetylcholine receptor 1; M1; Antagonist; ML012; VU0415248
18.  Discovery of N-Aryl Piperazines as Selective mGlu5 Potentiators with Efficacy in a Rodent Model Predictive of Anti-Psychotic Activity 
ACS medicinal chemistry letters  2010;1(8):433-438.
This Letter describes the discovery, SAR and in vitro and in vivo pharmacological profile of a novel non-MPEP derived mGlu5 positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGlu5 chemotype exhibits the ability to act as either a non-competitive antagonist/negative allosteric modulator (NAM) or potentiator of the glutamate response depending on the identity of the amide substituent, i.e., a ‘molecular switch’. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGlu5 receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of anti-psychotic activity, thus providing the first example of a centrally active mGluR5 PAM optimized from an HTS-derived mGluR5 competitive antagonist.
doi:10.1021/ml100181a
PMCID: PMC3539763  PMID: 23308336
mGluR; potentiator; positive allosteric modulator; schizophrenia; hyperlocomotion
19.  Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia 
Neuropsychopharmacology  2011;37(1):16-42.
Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M1 and M4) and nAChR (α7 and α2β4) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.
doi:10.1038/npp.2011.199
PMCID: PMC3238081  PMID: 21956443
acetylcholine; schizophrenia and antipsychotics; drug discovery and drug development; schizophrenia
20.  The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease 
ACS chemical neuroscience  2011;2(12):730-742.
T-type Ca2+ channel inhibitors hold tremendous therapeutic potential for the treatment of pain, epilepsy, sleep disorders, essential tremor and other neurological disorders; however, a lack of truly selective tools has hindered basic research, and selective tools from the pharmaceutical industry are potentially burdened with intellectual property (IP) constraints. Thus, an MLPCN high-throughput screen (HTS) was conducted to identify novel T-type Ca2+ channel inhibitors free from IP constraints, and freely available through the MLPCN, for use by the biomedical community to study T-type Ca2+ channels. While the HTS provided numerous hits, these compounds could not be optimized to the required level of potency to be appropriate tool compounds. Therefore, a scaffold hopping approach, guided by SurflexSim, ultimately afforded ML218 (CID 45115620) a selective T-Type Ca2+ (Cav3.1, Cav3.2, Cav3.3) inhibitor (Cav3.2, IC50 = 150 nM in Ca2+ flux; Cav3.2 IC50 = 310 nM and Cav3.3 IC50 = 270 nM, respectively in patch clamp electrophysiology) with good DMPK properties, acceptable in vivo rat PK and excellent brain levels. Electrophysiology studies in subthalamic nucleus (STN) neurons demonstrated robust effects of ML218 on the inhibition of T-Type calcium current, inhibition of low threshold spike and rebound burst activity. Based on the basal ganglia circuitry in Parkinson’s disease (PD), the effects of ML218 in STN neurons suggest a therapeutic role for T-type Ca2+ channel inhibitors, and ML218 was found to be orally efficacious in haloperidol-induced catalepsy, a preclinical PD model, with comparable efficacy to an A2A antagonist, a clinically validated PD target. ML218 proves to be a powerful new probe to study T-Type Ca2+ function in vitro and in vivo, and freely available.
doi:10.1021/cn200090z
PMCID: PMC3285241  PMID: 22368764
T-Type calcium channel; inhibitor; electrophysiology; Parkinson’s disease
21.  The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson’s Disease 
ACS Chemical Neuroscience  2011;2(12):730-742.
T-Type Ca2+ channel inhibitors hold tremendous therapeutic potential for the treatment of pain, epilepsy, sleep disorders, essential tremor, and other neurological disorders; however, a lack of truly selective tools has hindered basic research, and selective tools from the pharmaceutical industry are potentially burdened with intellectual property (IP) constraints. Thus, an MLPCN high-throughput screen (HTS) was conducted to identify novel T-type Ca2+ channel inhibitors free from IP constraints, and freely available through the MLPCN, for use by the biomedical community to study T-type Ca2+ channels. While the HTS provided numerous hits, these compounds could not be optimized to the required level of potency to be appropriate tool compounds. Therefore, a scaffold hopping approach, guided by SurflexSim, ultimately afforded ML218 (CID 45115620), a selective T-type Ca2+ (Cav3.1, Cav3.2, Cav3.3) inhibitor (Cav3.2, IC50 = 150 nM in Ca2+ flux; Cav3.2 IC50 = 310 nM; and Cav3.3 IC50 = 270 nM, respectively in patch clamp electrophysiology) with good DMPK properties, acceptable in vivo rat PK, and excellent brain levels. Electrophysiology studies in subthalamic nucleus (STN) neurons demonstrated robust effects of ML218 on the inhibition of T-type calcium current, inhibition of low threshold spike, and rebound burst activity. Based on the basal ganglia circuitry in Parkinson’s disease (PD), the effects of ML218 in STN neurons suggest a therapeutic role for T-type Ca2+ channel inhibitors, and ML218 was found to be orally efficacious in haloperidol-induced catalepsy, a preclinical PD model, with comparable efficacy to an A2A antagonist, a clinically validated PD target. ML218 proves to be a powerful new probe to study T-type Ca2+ function in vitro and in vivo, and freely available.
doi:10.1021/cn200090z
PMCID: PMC3285241  PMID: 22368764
T-Type calcium channel; inhibitor; electrophysiology; Parkinson’s disease
22.  Synthesis and SAR of centrally active mGlu5 positive allosteric modulators based on an aryl acetylenic bicyclic lactam scaffold 
This Letter describes the hit-to-lead progression and SAR of a series of biphenyl acetylene compounds derived from an HTS screening campaign targeting the mGlu5 receptor. ‘Molecular switches’ were identified that modulated modes of pharmacology, and several compounds within this series were shown to be efficacious in reversal of amphetamine induced hyperlocomotion in rats after i.p. dosing, a preclinical model that shows similar positive effects with known antipsychotic agents.
doi:10.1016/j.bmcl.2011.01.044
PMCID: PMC3498823  PMID: 21315585
23.  Discovery, Synthesis, SAR Development of a Series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4) with Oral Efficacy in an anti-Parkinsonian Animal Model 
Journal of medicinal chemistry  2011;54(21):7639-7647.
There is an increasing amount of literature data showing the positive effects on preclinical anti-Parkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4).1 However, most of the data generated utilize compounds that have not been optimized for drug-like properties and, as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)-phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established anti-Parkinsonian model.
doi:10.1021/jm200956q
PMCID: PMC3226828  PMID: 21966889
metabotropic glutamate receptors; mGlu4; positive allosteric modulators; Parkinson’s disease; haloperidol-induced catalepsy; structure-activity relationship (SAR); oral efficacy; brain penetration
24.  (3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu5: Discovery of a new tool compound with activity in the OSS mouse model of addiction 
ACS chemical neuroscience  2011;2(8):471-482.
Glutamate is the major excitatory transmitter in the mammalian CNS, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (Group I: mGlu1 and mGlu5; Group II: mGlu2 and mGlu3; Group III: mGlu4, mGlu6, mGlu7, and mGlu8). Non-competitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of SAR in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.
doi:10.1021/cn100099n
PMCID: PMC3172161  PMID: 21927650
mGlu5; negative allosteric modulator; non-competitive antagonist; addiction
25.  (3-Cyano-5-fluorophenyl)biaryl Negative Allosteric Modulators of mGlu5: Discovery of a New Tool Compound with Activity in the OSS Mouse Model of Addiction 
ACS Chemical Neuroscience  2011;2(8):471-482.
Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS), exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (group I: mGlu1 and mGlu5; group II: mGlu2 and mGlu3; group III: mGlu4, mGlu6, mGlu7, and mGlu8). Noncompetitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu5 offer potential therapeutic applications in diseases such as pain, anxiety, gastresophageal reflux disease (GERD), Parkinson’s disease (PD), fragile X syndrome, and addiction. The development of structure−activity relationships (SAR) in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu5 NAM in this novel assay.
doi:10.1021/cn100099n
PMCID: PMC3172161  PMID: 21927650
mGlu5; negative allosteric modulator; noncompetitive antagonist; addiction

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