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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Development of a Highly Selective, Orally Bioavailable and CNS Penetrant M1 Agonist Derived from the MLPCN Probe ML071 
Herein we report the discovery and SAR of a novel series of M1 agonists based on the MLPCN probe, ML071. From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M1 agonist with high selectivity, clean ancillary pharmacology and enantiospecific activity.
doi:10.1016/j.bmcl.2011.08.084
PMCID: PMC3190051  PMID: 21930376
Muscarinic acetylcholine receptor 1; mAChR1 (M1); ML071; Allosteric agonist
14.  Discovery, Synthesis, and Structure–Activity Relationship of a Series of N-Aryl-bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener 
ACS Chemical Neuroscience  2011;2(10):572-577.
Herein we report the discovery, synthesis, and evaluation of a series of N-aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (Kv7.2) and KCNQ4 (Kv7.4) channel openers. The best compound, 1 (ML213), has an EC50 of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profiles for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.
doi:10.1021/cn200065b
PMCID: PMC3223964  PMID: 22125664
KCNQ2; KCNQ4; activator; Kv7; ion channels; ML218; MLPCN probe
15.  Discovery, Synthesis, and Structure Activity Relationship of a Series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener 
ACS chemical neuroscience  2011;2(10):572-577.
Herein we report the discovery, synthesis and evaluation of a series of N-Aryl-bicyclo[2.2.1]heptane-2-carboxamides as selective KCNQ2 (Kv7.2) and KCNQ4 (Kv7.4) channel openers. The best compound, 1 (ML213) has an EC50 of 230 nM (KCNQ2) and 510 nM (KCNQ4) and is selective for KCNQ2 and KCNQ4 channels versus a large battery of related potassium channels, as well as affording modest brain levels. This represents the first report of unique selectivity profile for KCNQ2 and KCNQ4 over the other channels (KCNQ1/3/5) and as such should prove to be a valuable tool compound for understanding these channels in regulating neuronal activity.
doi:10.1021/cn200065b
PMCID: PMC3223964  PMID: 22125664
16.  Selective inhibition of the Kir2 family of inward rectifier potassium channels by a small molecule probe: the discovery, SAR and pharmacological characterization of ML133 
ACS chemical biology  2011;6(8):845-856.
The Kir inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (Kir1 – Kir7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective Kir2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of Kir2.1 function. Here we report one potent Kir2.1 inhibitor, ML133, which inhibits Kir2.1 with IC50 of 1.8 μM at pH 7.4 and 290 nM at pH 8.5, but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on Kir1.1 (IC50 > 300 μM), and displays weak activity for Kir4.1 (76 μM) and Kir7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the Kir family reported to date. Due to the high homology within the Kir family, the channels share a common design of a pore region flanked by two transmembrane domains, identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent Kir inhibitors. Using chimeric channels between Kir2.1 and Kir1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of Kir2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of Kir1.1 to those of Kir2.1 (N171D and C175I) transplants ML133 inhibition to Kir1.1. Together, the combination of a potent, Kir2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of Kir2 inward rectifier potassium channels.
doi:10.1021/cb200146a
PMCID: PMC3177608  PMID: 21615117
Kir2.1; inward rectifying potassium channel; ion channel; mutagenesis; structure-activity-relationship; medicinal chemistry; ion works; patch clamp; high throughput screening; MLPCN
17.  Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN Probe 
This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M1 PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M1 PAM with an in vitro profile comparable to the prototypical M1 PAM, BQCA, but with an improved brain to plasma ratio.
doi:10.1016/j.bmcl.2010.12.015
PMCID: PMC3082000  PMID: 21194936
18.  Thiol-Activated DNA Damage By α-Bromo-2-cyclopentenone 
Chemical Research in Toxicology  2011;24(2):217-228.
Some biologically active chemicals are relatively stable in the extracellular environment but, upon entering the cell, undergo biotransformation into reactive intermediates that covalently modify DNA. The diverse chemical reactions involved in the bioactivation of DNA-damaging agents are both fundamentally interesting and of practical importance in medicinal chemistry and toxicology. The work described here examines the bioactivation of α-haloacrolyl-containing molecules. The α-haloacrolyl moiety is found in a variety of cytotoxic natural products including clionastatin B, bromovulone III, discorahabdins A, B, and C, and trichodenone C, in mutagens such as 2-bromoacrolein and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and in the anticancer drug candidates brostallicin and PNU-151807. Using α-bromo-2-cyclopentenone (1) as a model compound, the activation of α-haloacrolyl-containing molecules by biological thiols was explored. The results indicate that both low molecular weight and peptide thiols readily undergo conjugate addition to 1. The resulting products are consistent with a mechanism in which initial addition of thiols to 1 is followed by intramolecular displacement of bromide ion to yield a DNA-alkylating episulfonium ion intermediate. The reaction of thiol-activated 1 with DNA produces labile lesions at deoxyguanosine residues. The sequence specificity and salt-dependence of this process is consistent with involvement of an episulfonium ion intermediate. The alkylated guanine residue resulting from the thiol-triggered reaction of 1 with duplex DNA was characterized using mass spectrometry. The results provide new insight regarding the mechanisms by which thiols can bioactivate small molecules and offer a more complete understanding of the molecular mechanisms underlying the biological activity of cytotoxic, mutagenic, and medicinal compounds containing the α-haloacrolyl group.
doi:10.1021/tx100282b
PMCID: PMC3268131  PMID: 21250671
19.  Design, Synthesis and Biological Evaluation of Halogenated N-(2-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethylbenzamides: Discovery of an Isoform-Selective Small Molecule Phospholipase D2 (PLD2) Inhibitor 
Journal of medicinal chemistry  2010;53(18):6706-6719.
Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD1 and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (>1,700-fold selective) and moderately PLD2 preferring (>10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC50 = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date, N-(2(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.
doi:10.1021/jm100814g
PMCID: PMC3179181  PMID: 20735042
phospholipase D; PLD; cancer; isoform; allosteric
20.  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
21.  DNA Strand Damage Product Analysis Provides Evidence that the Tumor Cell-Specific Cytotoxin Tirapazamine Produces Hydroxyl Radical and Acts as a Surrogate for O2 
The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) is a clinically-promising anticancer agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. It has long been known that, under hypoxic conditions, TPZ causes DNA strand damage that is initiated by the abstraction of hydrogen atoms from the deoxyribose phosphate backbone of duplex DNA but exact chemical mechanisms underlying this process remain unclear. Here we describe detailed characterization of sugar-derived products arising from TPZ-mediated strand damage. We find that the action of TPZ on duplex DNA under hypoxic conditions generates 5-methylene-2-furanone (6), oligonucleotide 3′-phosphoglycolates (7), malondialdehyde equivalents (8 or 9), and furfural (10). These results provide evidence that TPZ-mediated strand damage arises via hydrogen atom abstraction from both the most hindered (C1′) and least hindered (C4′ and C5′) positions of the deoxyribose sugars in the double helix. The products observed are identical to those produced by hydroxyl radical. Additional experiments were conducted to better understand the chemical pathways by which TPZ generates the observed DNA-damage products. Consistent with previous work showing that TPZ can substitute for molecular oxygen in DNA damage reactions, it is found that, under anaerobic conditions, reaction of TPZ with a discrete, photogenerated C1′-radical in a DNA 2′-oligodeoxynucleotide cleanly generates the 2-deoxyribonolactone lesion (5) that serves as the precursor to 5-methylene-2-furanone (6). Overall, the results provide insight regarding the chemical structure of the DNA lesions that confront cellular repair, transcription, and replication machinery following exposure to TPZ and offer new information relevant to the chemical mechanisms underlying TPZ-mediated strand cleavage.
doi:10.1021/ja074432m
PMCID: PMC2821206  PMID: 17900117
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.  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
25.  Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor 
This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M1 mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPα release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented.
doi:10.1016/j.bmcl.2012.03.088
PMCID: PMC3348459  PMID: 22507963
Muscarinic acetylcholine receptor 1; M1; Allosteric; Agonist; Bitopic; ML071; VU0364572

Results 1-25 (26)