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1.  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
2.  Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375) 
Journal of medicinal chemistry  2013;56(22):10.1021/jm4013246.
A functional high throughput screen and subsequent multi-dimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with sub-micromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1–4 IC50 >30 μM), excellent multi-species PK, high CNS penetration, and enantiospecific inhibition.
doi:10.1021/jm4013246
PMCID: PMC3876027  PMID: 24164599
Muscarinic acetylcholine receptor; M5; negative allosteric modulator (NAM); ML375; MLPCN probe
3.  Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: identification of ML300 and non-covalent nanomolar inhibitors with an induced-fit binding 
Bioorganic & medicinal chemistry letters  2013;23(22):10.1016/j.bmcl.2013.08.112.
Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2-S4 binding pockets leading to the first sub-micromolar non-covalent 3CLpro inhibitors retaining a single amide bond.
doi:10.1016/j.bmcl.2013.08.112
PMCID: PMC3878165  PMID: 24080461
3CLpro; severe acute respiratory syndrome; SARS; MERS; coronavirus
4.  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
5.  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) 
Journal of medicinal chemistry  2013;56(20):7976-7996.
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.
doi:10.1021/jm401028t
PMCID: PMC3908770  PMID: 24050755
6.  ML297 (VU0456810), the First Potent and Selective Activator of the GIRK Potassium Channel, Displays Antiepileptic Properties in Mice 
ACS Chemical Neuroscience  2013;4(9):1278-1286.
The G-protein activated, inward-rectifying potassium (K+) channels, “GIRKs”, are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels’ activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK’s role in physiology as well as providing the first tool for beginning to understand GIRK’s potential as a target for a diversity of therapeutic indications.
doi:10.1021/cn400062a
PMCID: PMC3778424  PMID: 23730969
GIRK; G-protein; inward rectifier; potassium channel; epilepsy; activator
7.  Octahydropyrrolo[3,4-c]pyrrole negative allosteric modulators of mGlu1 
Development of SAR in an octahydropyrrolo[3,4-c]pyrrole series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. The octahydropyrrolo[3,4-c]pyrrole scaffold was chosen as an isosteric replacement for the piperazine ring found in the initial hit compound. Characterization of selected compounds in protein binding assays was used to identify the most promising analogs, which were then profiled in P450 inhibition assays in order to further assess the potential for drug-likeness within this series of compounds.
doi:10.1016/j.bmcl.2013.07.029
PMCID: PMC3901432  PMID: 23932792
Glutamate; GPCR; mGlu1; Allosteric modulator; CNS; Octahydropyrrolo[3,4-c]pyrrole
8.  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
9.  N-Acyl-N′-arylpiperazines as negative allosteric modulators of mGlu1: Identification of VU0469650, a potent and selective tool compound with CNS exposure in rats 
Bioorganic & medicinal chemistry letters  2013;23(13):10.1016/j.bmcl.2013.05.020.
Development of SAR in an N-acyl-N′-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats.
doi:10.1016/j.bmcl.2013.05.020
PMCID: PMC3875306  PMID: 23727046
Glutamate; GPCR; mGlu1; Allosteric modulator; CNS; Piperazine
10.  Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 Selective and CNS Penetrant Negative Allosteric Modulator (NAM) 
Journal of medicinal chemistry  2013;56(12):5208-5212.
A multi-dimensional, iterative parallel synthesis effort identified a series of highly selective mGlu3 NAMs with sub-micromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.
doi:10.1021/jm400439t
PMCID: PMC3769689  PMID: 23718281
Metabotropic glutamate receptor; mGlu3; negative allosteric modulator (NAM); ML337; MLPCN probe
11.  Discovery of ML326: the first sub-micromolar, selective M5 PAM 
This letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10 μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409 nM and 480 nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s <30 μM) and a robust 20-fold leftward shift of the ACh CRC.
doi:10.1016/j.bmcl.2013.03.032
PMCID: PMC3634896  PMID: 23562060
Muscarinic acetylcholine receptors; M5; Positive allosteric modulator (PAM); ML326
12.  Enzymatic conversion of 6-nitroquinoline to the fluorophore 6-aminoquinoline selectively under hypoxic conditions 
Chemical research in toxicology  2013;26(4):555-563.
There is substantial interest in small molecules that can be used to detect or kill the hypoxic (low oxygen) cells found in solid tumors. Nitroaryl moieties are useful components in the design of hypoxia-selective imaging agents and prodrugs because one-electron reductases can convert the nitroaryl group to nitroso, hydroxylamino, and amino metabolites selectively under low oxygen conditions. Here we describe the in vitro, cell free metabolism of a pro-fluorescent substrate, 6-nitroquinoline (1) under both aerobic and hypoxic conditions. Both LC-MS and fluorescence spectroscopic analysis provided evidence that the one-electron reducing enzyme system, xanthine/xanthine oxidase, converted the nonfluorescent parent compound 1 to the known fluorophore 6-aminoquinoline (2) selectively under hypoxic conditions. The presumed intermediate in this reduction process, 6-hydroxylaminoquinoline (6) is fluorescent and can be efficiently converted by xanthine/xanthine oxidase to 2 only under hypoxic conditions. This finding provides evidence for multiple oxygen-sensitive steps in the enzymatic conversion of nitroaryl compounds to the corresponding amino derivatives. In a side reaction that is separate from the bioreductive metabolism of 1, xanthine oxidase converted 1 to 6-nitroquinolin-2(1H)-one (5). These studies may enable the use of 1 as a fluorescent substrate for the detection and profiling of one-electron reductases in cell culture or biopsy samples. In addition, the compound may find use as a fluorogenic probe for detection of hypoxia in tumor models. The occurrence of side products such as 5 in the enzymatic bioreduction of 1 underscores the importance of metabolite identification in the characterization of hypoxia-selective probes and drugs that employ nitroaryl units as oxygen sensors.
doi:10.1021/tx300483z
PMCID: PMC4003570  PMID: 23488987
13.  Development of Dual PLD1/2 and PLD2 Selective Inhibitors From a Common 1,3,8-Triazaspiro[4.5]decane Core: Discovery of ML298 and ML299 that Decrease Invasive Migration in U87-MG Glioblastoma Cells 
Journal of medicinal chemistry  2013;56(6):2695-2699.
An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 >20,000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core, and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.
doi:10.1021/jm301782e
PMCID: PMC3632306  PMID: 23445448
Phospholipase D; PLD1; PLD2; ML299; ML298; MLPCN probe
14.  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
15.  Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule 
This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6- membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype.
doi:10.1016/j.bmcl.2013.01.017
PMCID: PMC3594472  PMID: 23416001
Muscarinic acetylcholine receptor 1; M1; Spirocyclic; Positive allosteric modulator (PAM); ML137; VU0413162
16.  Isatin replacements applied to the highly selective, muscarinic M1 PAM ML137: Continued optimization of an MLPCN probe molecule 
This Letter describes the continued optimization of an MLPCN probe molecule (ML137) with a focused effort on the replacement/modification of the isatin moiety present in this highly selective M1 PAM. A diverse range of structures were validated as viable replacements for the isatin, many of which engendered sizeable improvements in their ability to enhance the potency and efficacy of acetylcholine when compared to ML137. Muscarinic receptor subtype selectivity for the M1 receptor was also maintained.
doi:10.1016/j.bmcl.2012.11.092
PMCID: PMC3534865  PMID: 23237839
Muscarinic acetylcholine receptor 1; M1; Allosteric; Positive allosteric modulator (PAM); ML137; VU0448350
17.  Development of novel M1 antagonist scaffolds through the continued optimization of the MLPCN probe ML012 
Bioorganic & medicinal chemistry letters  2012;22(15):10.1016/j.bmcl.2012.06.018.
This Letter describes the continued optimization of an MLPCN probe molecule M1 antagonist (ML012) through an iterative parallel synthesis approach. After several rounds of modifications of the parent compound, we arrived at a new azetidine scaffold that displayed improved potency while maintaining a desirable level of selectivity over other muscarinic receptor subtypes. Data for representative molecules 7w (VU0452865) and 12a (VU0455691) are presented.
doi:10.1016/j.bmcl.2012.06.018
PMCID: PMC3883446  PMID: 22749871
Muscarinic acetylcholine receptor 1; M1 Antagonist; ML012; VU0455691; VU0452865
18.  Development of an in vivo active, dual EP1 and EP3 selective antagonist based on a novel acyl sulfonamide bioisostere 
Recent preclinical studies demonstrate a role for the prostaglandin E2 (PGE2) subtype 1 (EP1) receptor in mediating, at least in part, the pathophysiology of hypertension and diabetes mellitus. A series of amide and N-acylsulfonamide analogs of a previously described picolinic acid-based human EP1 receptor antagonist (7) were prepared. Each analog had improved selectivity at the mouse EP1 receptor over the mouse thromboxane receptor (TP). A subset of analogs gained affinity for the mouse PGE2 subtype 3 (EP3) receptor, another potential therapeutic target. One analog (17) possessed equal selectivity for EP1 and EP3, displayed a sufficient in vivo residence time in mice, and lacked the potential for acyl glucuronide formation common to compound 7. Treatment of mice with 17 significantly attenuated the vasopressor activity resulting from an acute infusion of EP1 and EP3 receptor agonists. Compound 17 represents a potentially novel therapeutic in the treatment of hypertension and diabetes mellitus.
doi:10.1016/j.bmcl.2012.11.046
PMCID: PMC3534858  PMID: 23218714
Prostaglandin E2; EP1; EP3; Antagonist
19.  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
20.  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
21.  Targeting Selective Activation of M1 for the Treatment of Alzheimer’s Disease: Further Chemical Optimization and Pharmacological Characterization of the M1 Positive Allosteric Modulator ML169 
ACS Chemical Neuroscience  2012;3(11):884-895.
The M1 muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer’s disease (AD) and schizophrenia. Moreover, M1 interacts with BACE1 and regulates its proteosomal degradation, suggesting selective M1 activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M1 selective positive allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analogue libraries and probing novel scaffolds. We were able to identify several analogues that possessed submicromolar potency, with our best example displaying an EC50 of 310 nM. The new compounds maintained complete selectivity for the M1 receptor over the other subtypes (M2–M5), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogues were able to potentiate CCh-mediated nonamyloidogenic APPsα release, further strengthening the concept that M1 PAMs may afford a disease-modifying role in the treatment of AD.
doi:10.1021/cn300068s
PMCID: PMC3503349  PMID: 23173069
Muscarinic; acetylcholine; positive allosteric modulator (PAM); ML169; Alzheimer’s disease (AD); medium spiny neurons (MSNs); MLPCN
22.  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
23.  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
24.  Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: Development of a highly selective and more potent in vitro probe 
Further chemical optimization of the MLSCN/MLPCN probe ML077 (KCC2 IC50 = 537 nM) proved to be challenging as the effort was characterized by steep SAR. However, a multidimensional iterative parallel synthesis approach proved productive. Herein we report the discovery and SAR of an improved novel antagonist (VU0463271) of the neuronal-specific potassium-chloride cotransporter 2 (KCC2), with an IC50 of 61 nM and >100-fold selectivity versus the closely related Na-K-2Cl cotransporter 1 (NKCC1) and no activity in a larger panel of GPCRs, ion channels and transporters.
doi:10.1016/j.bmcl.2012.05.126
PMCID: PMC3389279  PMID: 22727639
Potassium-chloride co-transporter 2; KCC2; NKCC1; antagonist
25.  Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM 
Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) with 15-fold selectivity versus mGlu2. The mGlu3 NAM was discovered via a ‘molecular switch’ from a closely related, potent mGlu5 positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC50 value of 0.66 μM and is inactive against mGlu5. 2012
doi:10.1016/j.bmcl.2012.04.112
PMCID: PMC3365510  PMID: 22607673
metabotropic glutamate receptor 3; mGlu3; molecular switch; NAM

Results 1-25 (39)