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Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.
Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 1869-72
MeSH Terms: Allosteric Regulation, Central Nervous System, Coumarins, Dose-Response Relationship, Drug, Drug Discovery, Drug Stability, Furans, Humans, Isoindoles, Molecular Structure, Phthalimides, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added April 6, 2017
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.
Garcia-Barrantes PM, Cho HP, Metts AM, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 751-756
MeSH Terms: Allosteric Regulation, Animals, Antipsychotic Agents, Coumarins, Furans, Half-Life, Heterocyclic Compounds, Humans, Protein Binding, Rats, Receptors, Metabotropic Glutamate, Schizophrenia, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), driven by recent genetic data linking loss of function GRM1 to schizophrenia. Steep and caveat-laden SAR plagues the series, but ultimately potent mGlu1 PAMs (EC50s ∼5 nM) have resulted with good DMPK properties (low intrinsic clearance, clean CYP profile, modest Fu) and CNS penetration (Kps 0.25-0.97), along with up to >450-fold selectivity versus mGlu4 and mGlu5.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core.
Garcia-Barrantes PM, Cho HP, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2015) Bioorg Med Chem Lett 25: 5107-10
MeSH Terms: Allosteric Regulation, Animals, Brain, Coumarins, Furans, Humans, Microsomes, Liver, Phthalimides, Rats, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship
Show Abstract · Added February 18, 2016
This Letter describes the lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs). While first generation PAMs from Roche were reported in the late 1990s, little effort has focused on the development of mGlu1 PAMs since. New genetic data linking loss-of-function mutant mGlu1 receptors to schizophrenia, bipolar disorder and other neuropsychiatric disorders has rekindled interest in the target, but the ideal in vivo probe, for example, with good PK, brain penetration and low plasma protein binding, for robust target validation has been lacking. Here we describe the first modifications to the central aryl core of the VU0486321 series, where robust SAR was noted. Moreover, structural variants were identified that imparted selectivity (up to >793-fold) versus mGlu4.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
Toxicity studies of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide) as a colonoscopic imaging agent in rats.
Sakuma S, Kumagai H, Shimosato M, Kitamura T, Mohri K, Ikejima T, Hiwatari K, Koike S, Tobita E, McClure R, Gore JC, Pham W
(2015) Nanomedicine 11: 1227-36
MeSH Terms: Acetamides, Animals, Body Weight, CHO Cells, Caco-2 Cells, Colon, Colonoscopy, Colorectal Neoplasms, Coumarins, Cricetulus, Drinking, Eating, Fluorescent Dyes, Humans, Male, Nanospheres, Peanut Agglutinin, Polystyrenes, Polyvinyls, Rats, Rectum, Thiazoles
Show Abstract · Added February 15, 2016
UNLABELLED - We are investigating an imaging agent that detects early-stage primary colorectal cancer on the mucosal surface in real time under colonoscopic observation. The imaging agent, which is named the nanobeacon, is fluorescent nanospheres conjugated with peanut agglutinin and poly(N-vinylacetamide). Its potential use as an imaging tool for colorectal cancer has been thoroughly validated in numerous studies. Here, toxicities of the nanobeacon were assessed in rats. The nanobeacon was prepared according to the synthetic manner which is being established as the Good Manufacturing Practice-guided production. The rat study was performed in accordance with Good Laboratory Practice regulations. No nanobeacon treatment-related toxicity was observed. The no observable adverse effect levels (NOAEL) of the nanobeacon in 7-day consecutive oral administration and single intrarectal administration were estimated to be more than 1000mg/kg/day and 50mg/kg/day, respectively. We concluded that the nanobeacon could be developed as a safe diagnostic agent for colonoscopy applications.
FROM THE CLINICAL EDITOR - Colon cancer remains a major cause of death. Early detection can result in early treatment and thus survival. In this article, the authors tested potential systemic toxicity of coumarin 6-encapsulated polystyrene nanospheres conjugated with peanut agglutinin (PNA) and poly(N-vinylacetamide) (PNVA), which had been shown to bind specifically to colonic cancer cells and thus very promising in colonoscopic detection of cancer cells.
Copyright © 2015 Elsevier Inc. All rights reserved.
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2 Members
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22 MeSH Terms
High-throughput fluorescence assay of cytochrome P450 3A4.
Cheng Q, Guengerich FP
(2013) Methods Mol Biol 987: 157-62
MeSH Terms: Coumarins, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Enzyme Assays, Humans, Inhibitory Concentration 50, Ketoconazole, Spectrometry, Fluorescence
Show Abstract · Added March 26, 2014
Microtiter plate-based fluorescence assays allow rapid measurement of the catalytic activities of cytochrome P450 oxygenases (P450s). We describe a high-throughput fluorescence assay of P450 3A4, one of the key enzymes involved in xenobiotic metabolism. The assay involves the oxidative debenzylation of 7-hydroxy-4-trifluoromethyl coumarin, producing an increase in fluorescence.
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1 Members
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8 MeSH Terms
Multifunctional nanobeacon for imaging Thomsen-Friedenreich antigen-associated colorectal cancer.
Kumagai H, Pham W, Kataoka M, Hiwatari K, McBride J, Wilson KJ, Tachikawa H, Kimura R, Nakamura K, Liu EH, Gore JC, Sakuma S
(2013) Int J Cancer 132: 2107-17
MeSH Terms: Animals, Antigens, Tumor-Associated, Carbohydrate, Blotting, Western, Case-Control Studies, Colon, Colorectal Neoplasms, Coumarins, Diagnostic Imaging, Fluorescent Dyes, Humans, Immunoenzyme Techniques, Male, Mice, Mice, Transgenic, Nanospheres, Peanut Agglutinin, Polystyrenes, RNA, Messenger, Real-Time Polymerase Chain Reaction, Rectum, Reverse Transcriptase Polymerase Chain Reaction, Surface Properties, Thiazoles, Tissue Distribution, Tumor Cells, Cultured
Show Abstract · Added March 7, 2014
This research aimed to validate the specificity of the newly developed nanobeacon for imaging the Thomsen-Friedenreich (TF) antigen, a potential biomarker of colorectal cancer. The imaging agent is comprised of a submicron-sized polystyrene nanosphere encapsulated with a Coumarin 6 dye. The surface of the nanosphere was modified with peanut agglutinin (PNA) and poly(N-vinylacetamide (PNVA) moieties. The former binds to Gal-β(1-3)GalNAc with high affinity while the latter enhances the specificity of PNA for the carbohydrates. The specificity of the nanobeacon was evaluated in human colorectal cancer cells and specimens, and the data were compared with immunohistochemical staining and flow cytometric analysis. Additionally, distribution of the nanobeacon in vivo was assessed using an "intestinal loop" mouse model. Quantitative analysis of the data indicated that approximately 2 μg of PNA were detected for each milligram of the nanobeacon. The nanobeacon specifically reported colorectal tumors by recognizing the tumor-specific antigen through the surface-immobilized PNA. Removal of TF from human colorectal cancer cells and tissues resulted in a loss of fluorescence signal, which suggests the specificity of the probe. Most importantly, the probe was not absorbed systematically in the large intestine upon topical application. As a result, no registered toxicity was associated with the probe. These data demonstrate the potential use of this novel nanobeacon for imaging the TF antigen as a biomarker for the early detection and prediction of the progression of colorectal cancer at the molecular level.
Copyright © 2012 UICC.
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3 Members
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25 MeSH Terms
Lectin-immobilized fluorescent nanospheres for targeting to colorectal cancer from a physicochemical perspective.
Sakuma S, Yamashita S, Hiwatari K, Hoffman RM, Pham W
(2011) Curr Drug Discov Technol 8: 367-78
MeSH Terms: Acetamides, Animals, Colonoscopy, Colorectal Neoplasms, Coumarins, Drug Delivery Systems, Fluorescent Dyes, Humans, Nanospheres, Peanut Agglutinin, Polystyrenes, Polyvinyls, Thiazoles
Show Abstract · Added May 27, 2014
The goal of this research is to develop an imaging agent that enables real-time and accurate diagnosis of small-sized colorectal cancer. Since colorectal cancer initially develops in the mucous membrane of the large intestine, a nonabsorbable colonoscopic imaging agent capable of being administered intracolonically was designed. The imaging agent is peanut agglutinin (PNA)-immobilized polystyrene nanospheres with surface poly(N-vinylacetamide) (PNVA) chains encapsulating coumarin 6. PNA is a targeting moiety that binds to β-D-galactosyl-(1-3)-N-acetyl-D-galactosamine, which is the terminal sugar of the Thomsen-Friedenreich antigen that is specifically expressed on the mucosal side of colorectal cancer cells. PNVA is immobilized with the aim of reducing nonspecific interactions between the imaging agent and normal tissues, because the initial tumor-derived change is very small throughout the entire large intestine. Coumarin 6 is encapsulated into nanosphere cores to provide endoscopically-detectable fluorescence intensity. It is anticipated that the intracolonically-administered imaging agent recognizes tumor-derived changes in the large intestinal mucosa with high affinity and specificity. Real-time and accurate diagnosis of small-sized early colorectal cancer can be achieved through an imaging agent providing clear fluorescence contrast between normal and cancer tissues observed with a florescence endoscope. This review describes the design concept of this nanoprobe from a physicochemical perspective.
0 Communities
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13 MeSH Terms
Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay.
Pantel J, Williams SY, Mi D, Sebag J, Corbin JD, Weaver CD, Cone RD
(2011) Eur J Pharmacol 660: 139-47
MeSH Terms: Allosteric Regulation, Cyclic AMP, Drug Evaluation, Preclinical, Furocoumarins, HEK293 Cells, High-Throughput Screening Assays, Humans, Luminescent Measurements, Phosphodiesterase Inhibitors, Pilot Projects, Receptor, Melanocortin, Type 4, Reproducibility of Results, Signal Transduction, Structure-Activity Relationship, Sulfonamides, Time Factors
Show Abstract · Added December 10, 2013
The melanocortin MC(4) receptor is a potential target for the development of drugs for both obesity and cachexia. Melanocortin MC(4) receptor ligands known thus far are orthosteric agonists or antagonists, however the agonists, in particular, have generally exhibited unwanted side effects. For some receptors, allosteric modulators are expected to reduce side-effect profiles. To identify allosteric modulators of the melanocortin MC(4) receptor, we created HEK293 cell lines coexpressing the human melanocortin MC(4) receptor and a modified luciferase-based cAMP sensor. Monitoring luminescence as a readout of real-time intracellular cAMP concentration, we demonstrate that this cell line is able to report melanocortin agonist responses, as well as inverse agonist response to the physiological AgRP peptide. Based on the MC4R-GLO cell line, we developed an assay that was shown to meet HTS standards (Z'=0.50). A pilot screen run on the Microsource Spectrum compound library (n=2000) successfully identified 62 positive modulators. This screen identified predicted families of compounds: β(2)AR agonists - the β(2)AR being endogenously expressed in HEK293 cells, an adenylyl cyclase activator and finally a distribution of phosphodiesterase (PDE) inhibitors well characterized or recently identified. In this last category, we identified a structural family of coumarin-derived compounds (imperatorin, osthol and prenyletin), along with deracoxib, a drug in veterinary use for its COX2 inhibitory properties. This latter finding unveiled a new off-target mechanism of action for deracoxib as a PDE inhibitor. Overall, these data are the first report of a HTS for allosteric modulators for a Gs protein coupled receptor.
Copyright © 2011 Elsevier B.V. All rights reserved.
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3 Members
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16 MeSH Terms
A potential of peanut agglutinin-immobilized fluorescent nanospheres as a safe candidate of diagnostic drugs for colonoscopy.
Sakuma S, Kataoka M, Higashino H, Yano T, Masaoka Y, Yamashita S, Hiwatari K, Tachikawa H, Kimura R, Nakamura K, Kumagai H, Gore JC, Pham W
(2011) Eur J Pharm Sci 42: 340-7
MeSH Terms: Animals, Caco-2 Cells, Colon, Colonoscopy, Colorectal Neoplasms, Coumarins, Early Detection of Cancer, Female, Fluorescent Dyes, Humans, Indicators and Reagents, Intestinal Mucosa, Mice, Nanospheres, Peanut Agglutinin, Thiazoles
Show Abstract · Added May 27, 2014
We designed peanut agglutinin (PNA)-immobilized fluorescent nanospheres as a non-absorbable endoscopic imaging agent capable of being administered intracolonically. Following our previous researches with evidence that the imaging agent recognized small-sized colorectal tumors on the mucosal surface with high affinity and specificity in animal experiments, a potential of this nanoprobe as a drug candidate was evaluated from a safety perspective. The imaging agent detects colorectal tumors through recognition of the tumor-specific antigen by PNA immobilized on the nanosphere surface, and the detection is made via the fluorescent signal derived from coumarin 6 encapsulated into the nanosphere core. The stability studies revealed that the high activity of PNA was maintained and there was no significant leakage of coumarin 6 after intracolonic administration of the imaging agent. Cytotoxicity studies indicated that no local damage to the large intestinal membrane was induced by the imaging agent. Further, in vitro and in vivo permeation studies demonstrated that there was no significant permeation of the imaging agent through the monolayer of cultured cells and that the imaging agent administered locally to the luminal side of the large intestine was almost completely recovered from the administration site. Therefore, we concluded that the imaging agent is a safe and stable probe which remains in the large intestine without systemic exposure.
Copyright © 2011 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Basal lamina secreted by MDCK cells has size- and charge-selective properties.
Ferrell N, Groszek J, Li L, Smith R, Butler RS, Zorman CA, Roy S, Fissell WH
(2011) Am J Physiol Renal Physiol 300: F86-90
MeSH Terms: Animals, Basement Membrane, Cells, Cultured, Coumarins, Dogs, Extracellular Matrix, Ficoll, Fluorescein-5-isothiocyanate, Glomerular Basement Membrane, Kidney Glomerulus, Static Electricity
Show Abstract · Added August 21, 2013
The role electrical charge plays in determining glomerular permeability to macromolecules remains unclear. If the glomerular basement membrane (GBM) has any significant role in permselectivity, physical principles would suggest a negatively charged GBM would reject similarly charged more than neutral species. However, recent in vivo studies with negative and neutral glomerular probes showed the opposite. Whether this observation is due to unique characteristics of the probes used or is a general physiological phenomenon remains to be seen. The goal of this study was to use the basement membrane deposited by Madin-Darby canine kidney epithelial cells as a simple model of a biologically derived, negatively charged filter to evaluate size- and charge-based sieving properties. Fluorescein isothiocyanate-labeled carboxymethylated Ficoll 400 (FITC-CM Ficoll 400) and amino-4-methyl-coumarin-labeled Ficoll 400 (AMC Ficoll 400) were used as negatively charged and neutral tracer molecules, respectively, during pressure-driven filtration. Streaming potential measurement indicated the presence of fixed, negative charge in the basal lamina. The sieving coefficient for neutral Ficoll 400 decreased by ∼0.0013 for each 1-Å increment in solute radius, compared with a decrease of 0.0023 per Å for the anionic Ficoll 400. In this system, molecular charge played a significant role in determining the sieving characteristics of the membrane, pointing to solute charge as a potential contributor to GBM permselectivity.
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11 MeSH Terms