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Discovery of a novel 3,4-dimethylcinnoline carboxamide M positive allosteric modulator (PAM) chemotype via scaffold hopping.
Temple KJ, Engers JL, Long MF, Gregro AR, Watson KJ, Chang S, Jenkins MT, Luscombe VB, Rodriguez AL, Niswender CM, Bridges TM, Conn PJ, Engers DW, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 126678
MeSH Terms: Allosteric Regulation, Amides, Azetidines, Benzene, Molecular Structure, Protein Binding, Pyrazines, Pyridines, Pyrimidines, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M PAM activity and improved clearance and protein binding profiles.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Challenges in the development of an M PAM preclinical candidate: The discovery, SAR, and biological characterization of a series of azetidine-derived tertiary amides.
Tarr JC, Wood MR, Noetzel MJ, Melancon BJ, Lamsal A, Luscombe VB, Rodriguez AL, Byers FW, Chang S, Cho HP, Engers DW, Jones CK, Niswender CM, Wood MW, Brandon NJ, Duggan ME, Conn PJ, Bridges TM, Lindsley CW
(2017) Bioorg Med Chem Lett 27: 5179-5184
MeSH Terms: Allosteric Regulation, Amides, Azetidines, Drug Evaluation, Preclinical, Humans, Protein Binding, Pyridazines, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
Herein we describe the continued optimization of M positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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MeSH Terms
Challenges in the development of an M PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.
Tarr JC, Wood MR, Noetzel MJ, Bertron JL, Weiner RL, Rodriguez AL, Lamsal A, Byers FW, Chang S, Cho HP, Jones CK, Niswender CM, Wood MW, Brandon NJ, Duggan ME, Conn PJ, Bridges TM, Lindsley CW
(2017) Bioorg Med Chem Lett 27: 2990-2995
MeSH Terms: Allosteric Regulation, Amides, Animals, Azetidines, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Molecular Structure, Rats, Receptor, Muscarinic M4, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter details the continued chemical optimization of a novel series of M positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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MeSH Terms
Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach.
Burclaff J, Osaki LH, Liu D, Goldenring JR, Mills JC
(2017) Gastroenterology 152: 762-766.e7
MeSH Terms: Animals, Apoptosis, Atrophy, Azetidines, Cell Proliferation, Cellular Reprogramming, Chief Cells, Gastric, Diphtheria Toxin, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins, Intrinsic Factor, Metaplasia, Mice, Parietal Cells, Gastric, Peptides, Piperazines, Plant Lectins, Stomach, Tamoxifen
Show Abstract · Added April 18, 2017
Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.
Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.
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19 MeSH Terms
Loss of HGF activator inhibits foveolar hyperplasia induced by oxyntic atrophy without altering gastrin levels.
Yamagata Y, Aikou S, Fukushima T, Kataoka H, Seto Y, Esumi H, Kaminishi M, Goldenring JR, Nomura S
(2012) Am J Physiol Gastrointest Liver Physiol 303: G1254-61
MeSH Terms: Animals, Atrophy, Azetidines, Gastric Mucosa, Gastrins, Hyperplasia, Intercellular Signaling Peptides and Proteins, Male, Metaplasia, Mice, Mice, Knockout, Parietal Cells, Gastric, Peptides, Piperazines, Serine Endopeptidases
Show Abstract · Added September 3, 2013
Spasmolytic polypeptide/trefoil family factor 2 expressing metaplasia (SPEM) is induced by oxyntic atrophy and is known as a precancerous or paracancerous lesion. We now have sought to determine whether hepatocyte growth factor (HGF) influences the development of SPEM and oxyntic atrophy. DMP-777, a parietal cell ablating reagent, was administered to HGF activator (HGFA)-deficient mice and wild-type mice. Gastric mucosal lineage changes were analyzed in the DMP-777 treatment phase and recovery phase. Both wild-type and HGFA knockout mice showed SPEM, and there was no difference in SPEM development. However, after cessation of DMP-777, HGFA-deficient mice showed delayed recovery from SPEM compared with wild-type mice. Foveolar cell hyperplasia and the increase in proliferating cells after parietal cell loss were reduced in HGFA-deficient mice. The HGFA does not affect emergence of SPEM. However, the absence of HGFA signaling causes a delay in the recovery from SPEM to normal glandular composition. HGFA also promotes foveolar cell hyperplasia and mucosal cell proliferation in acute oxyntic injury.
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15 MeSH Terms
Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression.
Weis VG, Sousa JF, LaFleur BJ, Nam KT, Weis JA, Finke PE, Ameen NA, Fox JG, Goldenring JR
(2013) Gut 62: 1270-9
MeSH Terms: Animals, Azetidines, Biomarkers, Clusterin, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Helicobacter Infections, Humans, Inflammation, Intercellular Signaling Peptides and Proteins, Intestines, Laser Capture Microdissection, Metaplasia, Mice, Mice, Inbred CFTR, Parietal Cells, Gastric, Peptides, Piperazines, Precancerous Conditions, Up-Regulation
Show Abstract · Added October 7, 2013
OBJECTIVES - Spasmolytic polypeptide-expressing metaplasia (SPEM) develops as a preneoplastic lesion in the stomachs of mice and humans after parietal cell loss. To identify the commonalities and differences between phenotypic SPEM lineages, SPEM were studied from three different mouse models of parietal cell loss: with chronic inflammation with Helicobacter felis infection; with acute inflammation with L635 treatment; and without inflammation following DMP-777 treatment.
DESIGN - RNA transcripts from laser capture microdissected normal chief cells and SPEM lineages were compared using gene microarray. Alterations in transcripts were validated by quantitative real-time PCR. Clusterin and cystic fibrosis transmembrane conductance regulator (CFTR) were selected for immunohistochemical analysis in all mouse models as well as in human SPEM, intestinal metaplasia and gastric cancer.
RESULTS - Transcript expression patterns demonstrated differences among the phenotypic SPEM models. Clusterin expression was significantly upregulated in all three mouse SPEM models as well as in human SPEM. The highest clusterin expression in human gastric cancers correlated with poor survival. Conversely, CFTR expression was upregulated only in SPEM with inflammation in mice. In humans, intestinal metaplasia, but not SPEM, expressed CFTR.
CONCLUSIONS - While markers such as clusterin are expressed in all phenotypic SPEM lineages, distinct patterns of upregulated genes including CFTR are present in murine metaplasia associated with inflammation, indicative of progression of metaplasia towards a more intestinalised metaplastic phenotype.
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22 MeSH Terms
Development of novel M1 antagonist scaffolds through the continued optimization of the MLPCN probe ML012.
Melancon BJ, Utley TJ, Sevel C, Mattmann ME, Cheung YY, Bridges TM, Morrison RD, Sheffler DJ, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Wood MR
(2012) Bioorg Med Chem Lett 22: 5035-40
MeSH Terms: Animals, Azabicyclo Compounds, Azetidines, Cytochrome P-450 Enzyme System, Humans, Molecular Probes, Protein Binding, Protein Isoforms, Rats, Receptor, Muscarinic M1, Structure-Activity Relationship, Sulfonamides, Thiadiazoles
Show Abstract · Added March 7, 2014
This Paper describes the continued optimization of an MLPCN probe molecule M(1) 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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
1 Communities
3 Members
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13 MeSH Terms
Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells.
Nam KT, O'Neal RL, Coffey RJ, Finke PE, Barker N, Goldenring JR
(2012) Gut 61: 1678-85
MeSH Terms: Animals, Azetidines, Biomarkers, Biomarkers, Tumor, Cell Lineage, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Metaplasia, Mice, Parietal Cells, Gastric, Peptides, Piperazines, Precancerous Conditions, Receptors, G-Protein-Coupled, Stomach Neoplasms, beta-Galactosidase
Show Abstract · Added October 7, 2013
OBJECTIVE - Metaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa arises from transdifferentiation of mature gastric chief cells. Other investigations of intestinal progenitor cells have shown that cells demonstrating transcriptional activity for leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) in the intestine, colon and gastric antrum function as adult stem cells. We have now investigated whether cells demonstrating Lgr5 transcriptional activity in the oxyntic mucosa of mice might be responsible for development of metaplasia.
DESIGN - Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice were used to examine the distribution of Lgr5 transcriptionally active cells in the normal oxyntic mucosa as well as after treatment with DMP-777 or L-635 to induce acute SPEM. Lineage mapping was performed to determine if Lgr5-expressing cells gave rise to SPEM.
RESULTS - Cells expressing transcriptional activity for Lgr5 in the oxyntic mucosa were present as scattered rare cells only along the lesser curvature of the stomach. These cells also stained for markers of chief cells (intrinsic factor and pepsinogen) but never showed any staining for proliferative markers (Ki-67). In Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice induced with tamoxifen, treatment with either DMP-777 or L-635 to induce acute oxyntic atrophy caused induction of SPEM, but no lineage mapping into SPEM from Lgr5-expressing cells was observed.
CONCLUSION - The results indicate that, while chief cells with Lgr5 transcriptional activity are present along the lesser curvature of the gastric oxyntic mucosa, they are not responsible for production of metaplasia.
3 Communities
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16 MeSH Terms
Long-term efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidaemic patients with diabetes or metabolic syndrome.
Fazio S, Guyton JR, Lin J, Tomassini JE, Shah A, Tershakovec AM
(2010) Diabetes Obes Metab 12: 983-93
MeSH Terms: Anticholesteremic Agents, Azetidines, Cholesterol, LDL, Delayed-Action Preparations, Diabetes Mellitus, Type 2, Drug Combinations, Ezetimibe, Simvastatin Drug Combination, Female, Humans, Hyperlipidemias, Male, Metabolic Syndrome, Middle Aged, Niacin, Simvastatin, Treatment Outcome
Show Abstract · Added December 10, 2013
AIMS - To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended-release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non-DM) or neither (non-DM/non-MetS).
METHODS - A subgroup analysis of a double-blind, 64-week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2-g dose were included in the analysis.
RESULTS - E/S+N improved levels of low-density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high-density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high-sensitivity C-reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New-onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N-containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during the 24-64 week extension study, diabetes was diagnosed in five additional patients in the E/S(cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%). Treatment-incident elevations in uric acid levels were increased among subjects assigned to N-containing regimens, but there were no effects on symptomatic gout.
CONCLUSION - Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels.
© 2010 Blackwell Publishing Ltd.
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16 MeSH Terms
Long-term safety and efficacy of triple combination ezetimibe/simvastatin plus extended-release niacin in patients with hyperlipidemia.
Fazio S, Guyton JR, Polis AB, Adewale AJ, Tomassini JE, Ryan NW, Tershakovec AM
(2010) Am J Cardiol 105: 487-94
MeSH Terms: Adolescent, Adult, Aged, Azetidines, Biomarkers, C-Reactive Protein, Cholesterol, HDL, Cholesterol, LDL, Delayed-Action Preparations, Double-Blind Method, Drug Therapy, Combination, Ezetimibe, Female, Follow-Up Studies, Humans, Hyperlipidemias, Hypolipidemic Agents, Lipoproteins, Male, Middle Aged, Niacin, Severity of Illness Index, Simvastatin, Tennessee, Time Factors, Treatment Outcome, Vitamin B Complex
Show Abstract · Added December 10, 2013
The safety and efficacy of combination ezetimibe/simvastatin (E/S) plus extended-release niacin was assessed in 942 patients with type IIa/IIb hyperlipidemia for 64 weeks in a randomized, double-blind study. Patients received E/S (10/20 mg) plus niacin (to 2 g) or E/S (10/20 mg) for 64 weeks, or niacin (to 2 g) for 24 weeks and then E/S (10/20 mg) plus niacin (2 g) or E/S (10/20 mg) for an additional 40 weeks. The primary end point, the safety of E/S plus niacin, included prespecified adverse events (ie, liver, muscle, discontinuations due to flushing, gallbladder-related, cholecystectomy, fasting glucose changes, new-onset diabetes). The secondary end points included the percentage of change from baseline in high-density lipoprotein (HDL) cholesterol, triglycerides, non-HDL cholesterol, and low-density lipoprotein cholesterol, other lipids, lipoprotein ratios and high-sensitivity C-reactive protein. The anticipated niacin-associated flushing led to a greater rate of study discontinuations with the E/S plus niacin regimen than with E/S alone (0.7%, p <0.001). The rate of liver and muscle adverse events was low (<1%) in both groups. Four patients had gallbladder-related adverse events; 1 patient in the E/S and 1 in the E/S plus niacin group underwent cholecystectomy. The occurrence of new-onset diabetes was 3.1% for the E/S and 4.9% for the E/S plus niacin group. The fasting glucose levels increased to greater than baseline during the first 12 weeks (E/S, 3.2 mg/dl; E/S plus niacin, 7.7 mg/dl) and gradually decreased to pretreatment levels by 64 weeks in both groups. E/S plus niacin significantly improved HDL cholesterol, triglycerides, non-HDL cholesterol, low-density lipoprotein cholesterol, apolipoprotein B and A-I, and lipoprotein ratios compared with E/S (p Copyright 2010 Elsevier Inc. All rights reserved.
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27 MeSH Terms