7 results on '"Sonatore L"'
Search Results
2. Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors.
- Author
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Cernak T, Gesmundo NJ, Dykstra K, Yu Y, Wu Z, Shi ZC, Vachal P, Sperbeck D, He S, Murphy BA, Sonatore L, Williams S, Madeira M, Verras A, Reiter M, Lee CH, Cuff J, Sherer EC, Kuethe J, Goble S, Perrotto N, Pinto S, Shen DM, Nargund R, Balkovec J, DeVita RJ, and Dreher SD
- Subjects
- Chromatography, Liquid, Mass Spectrometry, Proton Magnetic Resonance Spectroscopy, Diacylglycerol O-Acyltransferase antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology
- Abstract
Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging S
N Ar reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.- Published
- 2017
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3. Potential mechanism of enhanced postprandial glucagon-like peptide-1 release following treatment with a diacylglycerol acyltransferase 1 inhibitor.
- Author
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Liu J, McLaren DG, Chen D, Kan Y, Stout SJ, Shen X, Murphy BA, Forrest G, Karanam B, Sonatore L, He S, Roddy TP, and Pinto S
- Abstract
Studies have demonstrated that blockade of diacylglycerol acyltransferase 1 (DGAT1) leads to prolonged release of glucagon-like peptide 1 (GLP-1) after meal challenge. The current study was undertaken to investigate the mechanism of action underlying the elevated levels of GLP-1 release following pharmacological inhibition of DGAT1. We utilized a potent, specific DGAT1 inhibitor, compound A , to investigate the changes in intestinal lipid profile in a mouse model after oral administration of the compound and challenge with tracer containing fatty meal. [
13 C18 ]-oleic acid and LC-MS were employed to trace the fate of dietary fatty acids provided as part of a meal challenge in lean mice. Lipid profiles in plasma, proximal to distal segments of intestine, and feces were evaluated at various times following the meal challenge to study the kinetics of fatty acid absorption, synthesis into complex lipids, and excretion. Pharmacological inhibition of DGAT1 led to reduction of postprandial total and newly synthesized triglyceride (TG) excursion and significant increases in TG and FFA levels in the distal portion of intestine enriched with enteroendocrine L cells. Enhanced levels of FFA and cholesteryl ester were observed via fecal fat profiling. DGAT1 inhibition leads to enhancement of carbon flow to the synthesis of phosphatidylcholine within the intestine. DGAT1 inhibition markedly increases levels of TG and FFA in the distal intestine, which could be the predominant contributor to the prolonged and enhanced postprandial GLP-1 release. Inactivation of DGAT1 could provide potential benefit in the treatment of dysmetabolic diseases.- Published
- 2015
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4. Rapid development of two factor IXa inhibitors from hit to lead.
- Author
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Parker DL Jr, Walsh S, Li B, Kim E, Sharipour A, Smith C, Chen YH, Berger R, Harper B, Zhang T, Park M, Shu M, Wu J, Xu J, Dewnani S, Sherer EC, Hruza A, Reichert P, Geissler W, Sonatore L, Ellsworth K, Balkovec J, Greenlee W, and Wood HB
- Subjects
- Binding Sites, Drug Discovery, Humans, Models, Molecular, Molecular Structure, Protein Conformation, Anticoagulants chemistry, Anticoagulants pharmacology, Factor IXa antagonists & inhibitors
- Abstract
Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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5. Heterocyclic core analogs of a direct thrombin inhibitor.
- Author
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Blizzard TA, Singh S, Patil B, Chidurala N, Komanduri V, Debnath S, Belyakov S, Crespo A, Struck A, Kurtz M, Wiltsie J, Shen X, Sonatore L, Arocho M, Lewis D, Ogletree M, and Biftu T
- Subjects
- Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Heterocyclic Compounds chemical synthesis, Heterocyclic Compounds chemistry, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Thrombin metabolism, Enzyme Inhibitors pharmacology, Heterocyclic Compounds pharmacology, Thrombin antagonists & inhibitors
- Abstract
Thrombin is a serine protease that plays a key role in blood clotting. Pyrrolidine 1 is a potent thrombin inhibitor discovered at Merck several years ago. Seven analogs (2-8) of 1 in which the pyrrolidine core was replaced with various heterocycles were prepared and evaluated for activity against thrombin, clotting factors VIIa, IXa, Xa, and XIIa, and trypsin. The thiomorpholine analog 6 was the most active, essentially matching the thrombin inhibitory activity of 1 with slightly improved selectivity over trypsin., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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6. Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release--potential insight into mechanism of action.
- Author
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Liu J, Gorski JN, Gold SJ, Chen D, Chen S, Forrest G, Itoh Y, Marsh DJ, McLaren DG, Shen Z, Sonatore L, Carballo-Jane E, Craw S, Guan X, Karanam B, Sakaki J, Szeto D, Tong X, Xiao J, Yoshimoto R, Yu H, Roddy TP, Balkovec J, and Pinto S
- Subjects
- Animals, Body Composition, Chromatography, Liquid, Diacylglycerol O-Acyltransferase antagonists & inhibitors, Diacylglycerol O-Acyltransferase genetics, Disease Models, Animal, Dogs, Enteroendocrine Cells drug effects, Enteroendocrine Cells metabolism, Feces chemistry, Gastrointestinal Tract metabolism, Ginsenosides pharmacology, HT29 Cells, Hormones metabolism, Humans, Immunohistochemistry, Lactones pharmacology, Male, Mice, Mice, Inbred C57BL, Orlistat, Postprandial Period drug effects, Tandem Mass Spectrometry, Triglycerides blood, Body Weight drug effects, Diacylglycerol O-Acyltransferase metabolism, Gastrointestinal Tract drug effects
- Abstract
Objective: Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L., Design and Methods: Biochemical and stable-label tracer approaches were applied to interrogate the functional activities of compounds K and L on TG synthesis and changes of carbon flow. Energy homeostasis and gut peptide release upon DGAT1 inhibition was conducted in mouse and dog models., Results: Compounds K and L, dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies in WT and Dgat1(-/-) mice, confirmed that the effects of compound K on body weight loss is mechanism-based. Compounds K and L altered incretin peptide release following oral fat challenge. Immunohistochemical studies with intestinal tissues demonstrate lack of detectable DGAT1 immunoreactivity in enteroendocrine cells. Furthermore, (13) C-fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC)., Conclusion: Treatment with DGAT1 inhibitors improves lipid metabolism and body weight. DGAT1 inhibition leads to enhanced PC production via alternative carbon channeling. Immunohistological studies suggest that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Overall these data indicate a translational potential towards the clinic., (Copyright © 2012 The Obesity Society.)
- Published
- 2013
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7. The utility of FK506-binding protein as a fusion partner in scintillation proximity assays: application to SH2 domains.
- Author
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Sonatore LM, Wisniewski D, Frank LJ, Cameron PM, Hermes JD, Marcy AI, and Salowe SP
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- Amino Acid Sequence, Biotin chemistry, DNA-Directed RNA Polymerases genetics, Escherichia coli genetics, Escherichia coli metabolism, Genetic Vectors, Ligands, Molecular Sequence Data, Phosphopeptides chemistry, Recombinant Fusion Proteins chemistry, Tacrolimus chemistry, Tacrolimus Binding Proteins, Tritium, Viral Proteins, Carrier Proteins biosynthesis, Carrier Proteins chemistry, DNA-Binding Proteins biosynthesis, DNA-Binding Proteins chemistry, Heat-Shock Proteins biosynthesis, Heat-Shock Proteins chemistry, Recombinant Fusion Proteins biosynthesis, Scintillation Counting, src Homology Domains
- Abstract
Methodology has been developed which gives a specific measure of the interaction of an SH2 domain with a phosphopeptide ligand using scintillation proximity assay (SPA) technology. Recombinant SH2 domains were expressed from a T7 RNA polymerase-based vector in Escherichia coli as fusions to the C-terminus of the FK506-binding protein (FKBP) and purified from freeze-thaw lysates in high yield by affinity chromatography using immobilized phosphopeptides. For binding assays the phosphopeptide ligands were synthesized with a biotin tag and the FKBP fusion proteins were noncovalently radiolabeled with commercially available [3H]dihydroFK506. Complexes of tritiated SH2 fusion protein and biotinyl-phosphopeptide were then captured on streptavidin-coated SPA beads and counted. The modular protocol is an equilibrium technique that does not employ washing steps or specialized radiochemical syntheses required in other binding assays. The utility of the assay has been demonstrated in an examination of the ligand specificity of the SH2 domains of the tyrosine kinases ZAP70, Syk, and Lck. The methodology is potentially generalizable to any receptor-ligand interaction in which one component can be expressed as a fusion partner with FKBP and the other component can be captured on a SPA bead.
- Published
- 1996
- Full Text
- View/download PDF
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