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Surveying heterocycles as amide bioisosteres within a series of mGlu NAMs: Discovery of VU6019278.
Reed CW, Washecheck JP, Quitlag MC, Jenkins MT, Rodriguez AL, Engers DW, Blobaum AL, Jeffrey Conn P, Niswender CM, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 1211-1214
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Hepatocytes, Heterocyclic Compounds, Inhibitory Concentration 50, Pyrazoles, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu NAM chemotype led to the discovery of VU6019278, a potent mGlu NAM (IC = 501 nM, 6.3% L-AP Min) with favorable plasma protein binding (rat f = 0.10), low predicted hepatic clearance (rat CL = 27.7 mL/min/kg) and high CNS penetration (rat K = 4.9, K = 0.65).
Copyright © 2019 Elsevier Ltd. All rights reserved.
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Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a]pyrimidine-5-carboxamide and Thieno[3,2- b]pyridine-5-carboxamide Cores.
Childress ES, Wieting JM, Felts AS, Breiner MM, Long MF, Luscombe VB, Rodriguez AL, Cho HP, Blobaum AL, Niswender CM, Emmitte KA, Conn PJ, Lindsley CW
(2019) J Med Chem 62: 378-384
MeSH Terms: Allosteric Regulation, Amides, Animals, Central Nervous System, Drug Evaluation, Preclinical, Half-Life, Humans, Inhibitory Concentration 50, Protein Isoforms, Pyrazoles, Pyridines, Pyrimidines, Rats, Receptors, Metabotropic Glutamate, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
A scaffold hopping exercise from a monocyclic mGlu NAM with poor rodent PK led to two novel heterobicyclic series of mGlu NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu NAM potency, selectivity (versus mGlu and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.
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Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5.
Felts AS, Rodriguez AL, Morrison RD, Bollinger KA, Venable DF, Blobaum AL, Byers FW, Thompson Gray A, Daniels JS, Niswender CM, Jones CK, Conn PJ, Lindsley CW, Emmitte KA
(2017) Bioorg Med Chem Lett 27: 4858-4866
MeSH Terms: Allosteric Regulation, Amides, Animals, Cell Membrane Permeability, Dogs, Dopamine Plasma Membrane Transport Proteins, Drug Evaluation, Preclinical, Half-Life, Humans, Inhibitory Concentration 50, Madin Darby Canine Kidney Cells, Mice, Microsomes, Liver, Pyridines, Rats, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship, Triazoles
Show Abstract · Added March 3, 2020
Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu versus DAT.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line.
Bryan MR, Uhouse MA, Nordham KD, Joshi P, Rose DIR, O'Brien MT, Aschner M, Bowman AB
(2018) Neurotoxicology 64: 185-194
MeSH Terms: Animals, Cell Line, Chromones, Corpus Striatum, HEK293 Cells, Homeostasis, Humans, Induced Pluripotent Stem Cells, Inhibitory Concentration 50, Manganese, Mice, Morpholines, Neural Stem Cells, Phosphatidylinositol 3-Kinase, Signal Transduction, Tumor Suppressor Protein p53
Show Abstract · Added April 11, 2018
In a recent study, we found that blocking the protein kinase ataxia telangiectasia mutated (ATM) with the small molecule inhibitor (SMI) KU-55933 can completely abrogate Mn-induced phosphorylation of p53 at serine 15 (p-p53) in human induced pluripotent stem cell (hiPSC)-differentiated striatal neuroprogenitors. However, in the immortalized mouse striatal progenitor cell line STHdh, a concentration of KU55933 far exceeding its IC for ATM was required to inhibit Mn-induced p-p53. This suggested an alternative signaling system redundant with ATM kinase for activating p53 in this cell line- one that was altered by KU55933 at these higher concentrations (i.e. mTORC1, DNApk, PI3K). To test the hypothesis that one or more of these signaling pathways contributed to Mn-induced p-p53, we utilized a set of SMIs (e.g. NU7441 and LY294002) known to block DNApk, PI3K, and mTORC1 at distinct concentrations. We found that the SMIs inhibit Mn-induced p-p53 expression near the expected IC for PI3K, versus other known targets. We hypothesized that inhibiting PI3K reduces intracellular Mn and thereby decreases activation of p53 by Mn. Using the cellular fura-2 manganese extraction assay (CFMEA), we determined that KU55933/60019, NU7441, and LY294002 (at concentrations near their IC for PI3K) all decrease intracellular Mn (∼50%) after a dual, 24-h Mn and SMI exposure. Many pathways are activated by Mn aside from p-p53, including AKT and mTOR pathways. Thus, we explored the activation of these pathways by Mn in STHdh cells as well as the effects of other pathway inhibitors. p-AKT and p-S6 activation by Mn is almost completely blocked upon addition of NU7441(5μM) or LY294002(7μM), supporting PI3K's upstream role in the AKT/mTOR pathway. We also investigated whether PI3K inhibition blocks Mn uptake in other cell lines. LY294002 exposure did not reduce Mn uptake in ST14A, Neuro2A, HEK293, MEF, or hiPSC-derived neuroprogenitors. Next, we sought to determine whether inhibition of PI3K blocked p53 phosphorylation by directly blocking an unknown PI3K/p53 interaction or indirectly reducing intracellular Mn, decreasing p-p53 expression. In-Cell Western and CFMEA experiments using multiple concentrations of Mn exposures demonstrated that intracellular Mn levels directly correlated with p-p53 expression with or without addition of LY294002. Finally, we examined whether PI3K inhibition was able to block Mn-induced p-p53 activity in hiPSC-derived striatal neuroprogenitors. As expected, LY294002 does not block Mn-induced p-p53 as PI3K inhibition is unable to reduce Mn net uptake in this cell line, suggesting the effect of LY294002 on Mn uptake is relatively specific to the STHdh mouse striatal cell line.
Copyright © 2017 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.
Bender AM, Weiner RL, Luscombe VB, Cho HP, Niswender CM, Engers DW, Bridges TM, Conn PJ, Lindsley CW
(2017) Bioorg Med Chem Lett 27: 2479-2483
MeSH Terms: Animals, Brain, Humans, Inhibitory Concentration 50, Muscarinic Antagonists, Protein Binding, Pyrimidines, Rats, Receptor, Muscarinic M4, Receptors, Muscarinic, Recombinant Proteins, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M (ICs<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CL=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires.
Tian M, Cheng C, Chen X, Duan H, Cheng HL, Dao M, Sheng Z, Kimble M, Wang L, Lin S, Schmidt SD, Du Z, Joyce MG, Chen Y, DeKosky BJ, Chen Y, Normandin E, Cantor E, Chen RE, Doria-Rose NA, Zhang Y, Shi W, Kong WP, Choe M, Henry AR, Laboune F, Georgiev IS, Huang PY, Jain S, McGuire AT, Georgeson E, Menis S, Douek DC, Schief WR, Stamatatos L, Kwong PD, Shapiro L, Haynes BF, Mascola JR, Alt FW
(2016) Cell 166: 1471-1484.e18
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, Broadly Neutralizing Antibodies, Cell Line, Disease Models, Animal, Gene Expression Regulation, HIV Antibodies, HIV-1, Immunization, Immunoglobulin Heavy Chains, Inhibitory Concentration 50, Mice, Precursor Cells, B-Lymphoid, Sequence Deletion, T-Lymphocytes
Show Abstract · Added May 3, 2017
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2(∗)02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.
Copyright © 2016 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Optimization of the choline transporter (CHT) inhibitor ML352: Development of VU6001221, an improved in vivo tool compound.
Bertron JL, Ennis EA, Tarr CJ, Wright J, Dickerson JW, Locuson CW, Blobaum AL, Rook JM, Blakely RD, Lindsley CW
(2016) Bioorg Med Chem Lett 26: 4637-4640
MeSH Terms: Animals, Benzamides, Dose-Response Relationship, Drug, Half-Life, Inhibitory Concentration 50, Isoxazoles, Membrane Transport Proteins, Oxazoles, Piperidines, Rats, Structure-Activity Relationship
Show Abstract · Added March 21, 2018
This Letter describes the further lead optimization of the CHT inhibitor probe, ML352 (VU0476201), and the development of VU6001221, an improved in vivo tool. A multi-dimensional optimization effort encountered steep SAR, and ultimately, subtle tuning of the electronics of the central phenyl core provided VU6001221, a CHT inhibitor with comparable potency for choline uptake inhibition as ML352, yet improved PK and CNS penetration. Moreover, VU6001221 enabled evaluation, for the first time, of a CHT inhibitor in a standard preclinical rodent cognition model, novel object recognition (NOR). We observed VU6001221 to elicit a dose-responsive increase in NOR, raising the possibility of agonism of synaptic α7 nicotinic ACh receptors by elevated extracellular choline, that if confirmed would represent a novel molecular strategy to enhance cognition.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus.
Smith SA, Silva LA, Fox JM, Flyak AI, Kose N, Sapparapu G, Khomandiak S, Khomadiak S, Ashbrook AW, Kahle KM, Fong RH, Swayne S, Doranz BJ, McGee CE, Heise MT, Pal P, Brien JD, Austin SK, Diamond MS, Dermody TS, Crowe JE
(2015) Cell Host Microbe 18: 86-95
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Chemoprevention, Chikungunya Fever, Chikungunya virus, Disease Models, Animal, Humans, Immunization, Passive, Inhibitory Concentration 50, Mice, Protein Binding, Survival Analysis, Treatment Outcome, Viral Envelope Proteins, Virus Internalization
Show Abstract · Added January 26, 2016
Chikungunya virus (CHIKV) is a mosquito-transmitted RNA virus that causes acute febrile infection associated with polyarthralgia in humans. Mechanisms of protective immunity against CHIKV are poorly understood, and no effective therapeutics or vaccines are available. We isolated and characterized human monoclonal antibodies (mAbs) that neutralize CHIKV infectivity. Among the 30 mAbs isolated, 13 had broad and ultrapotent neutralizing activity (IC50 < 10 ng/ml), and all of these mapped to domain A of the E2 envelope protein. Potent inhibitory mAbs blocked post-attachment steps required for CHIKV membrane fusion, and several were protective in a lethal challenge model in immunocompromised mice, even when administered at late time points after infection. These highly protective mAbs could be considered for prevention or treatment of CHIKV infection, and their epitope location in domain A of E2 could be targeted for rational structure-based vaccine development.
Copyright © 2015 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Channel Activity of Cardiac Ryanodine Receptors (RyR2) Determines Potency and Efficacy of Flecainide and R-Propafenone against Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes.
Savio-Galimberti E, Knollmann BC
(2015) PLoS One 10: e0131179
MeSH Terms: Animals, Arrhythmias, Cardiac, Caffeine, Calcium, Calcium Signaling, Calsequestrin, Cell Membrane Permeability, Flecainide, Heart Ventricles, Humans, Inhibitory Concentration 50, Male, Mice, Inbred C57BL, Myocytes, Cardiac, Propafenone, Rabbits, Ryanodine Receptor Calcium Release Channel, Tetracaine
Show Abstract · Added February 22, 2016
Flecainide blocks ryanodine receptor type 2 (RyR2) channels in the open state, suppresses arrhythmogenic Ca2+ waves and prevents catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice and humans. We hypothesized that differences in RyR2 activity induced by CPVT mutations determines the potency of open-state RyR2 blockers like flecainide (FLEC) and R-propafenone (RPROP) against Ca2+ waves in cardiomyocytes. Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits). Consistent with increased RyR2 activity, Ca2+ spark and wave frequencies were significantly higher in CPVT compared to WT mouse myocytes. We next obtained concentration-response curves of Ca2+ wave inhibition for FLEC, RPROP (another open-state RyR2 blocker), and tetracaine (TET) (a state-independent RyR2 blocker). Both FLEC and RPROP inhibited Ca2+ waves with significantly higher potency (lower IC50) and efficacy in CPVT compared to WT. In contrast, TET had similar potency in all groups studied. Increasing RyR2 activity of permeabilized WT myocytes by exposure to caffeine (150 µM) increased the potency of FLEC and RPROP but not of TET. RPROP and FLEC were also significantly more potent in rabbit ventricular myocytes that intrinsically exhibit higher Ca2+ spark rates than WT mouse ventricular myocytes. In conclusion, RyR2 activity determines the potency of open-state blockers FLEC and RPROP for suppressing arrhythmogenic Ca2+ waves in cardiomyocytes, a mechanism likely relevant to antiarrhythmic drug efficacy in CPVT.
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18 MeSH Terms
Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.
Wirtz ED, Hoshino D, Maldonado AT, Tyson DR, Weaver AM
(2015) JAMA Otolaryngol Head Neck Surg 141: 543-9
MeSH Terms: Benzoquinones, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Survival, Class I Phosphatidylinositol 3-Kinases, Head and Neck Neoplasms, Humans, Imidazoles, Indazoles, Inhibitory Concentration 50, Lactams, Macrocyclic, Molecular Targeted Therapy, Mutation, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Pyridones, Pyrimidinones, Quinolines, Squamous Cell Carcinoma of Head and Neck, Sulfonamides, TOR Serine-Threonine Kinases, Tumor Cells, Cultured
Show Abstract · Added February 15, 2016
IMPORTANCE - The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation.
OBJECTIVES - (1) To determine the role of oncogene dependence on PIK3CA-one of the more common and targetable oncogenes in HNSCC, and (2) to evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies.
DESIGN, SETTING, AND PARTICIPANTS - This was a cell culture-based, in vitro study performed at an academic research laboratory assessing the viability of PIK3CA-mutated head and neck cell lines when treated with targeted therapy.
EXPOSURES - PIK3CA-mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235.
MAIN OUTCOMES AND MEASURES - Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R.
RESULTS - Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred increased, rather than reduced, IC50 assay measurements when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared with the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared with control, whereas those expressing E545K showed slightly increased sensitivity of unclear significance.
CONCLUSIONS AND RELEVANCE - (1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared with control with dual PI3K/mTOR inhibition. (2) Oncogene addiction to PIK3CA hotspot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified. Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of PI3K-overactive HNSCC tumors.
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22 MeSH Terms