The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Craig W. Lindsley - One of the best experts on this subject based on the ideXlab platform.
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discovery of r 2 fluoro 4 4 methoxyphenyl ethynyl phenyl 3 hydroxypiperidin 1 yl methanone ml337 an mglu3 selective and cns penetrant negative allosteric modulator nam
Journal of Medicinal Chemistry, 2013Co-Authors: Cody J Wenthur, Jeffrey P Conn, Scott J Daniels, Ryan D Morrison, Andrew S Felts, Katrina A Smith, Julie L Engers, Frank W Byers, Kyle A Emmitte, Craig W. LindsleyAbstract:A multidimensional, iterative Parallel Synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.
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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, 2013Co-Authors: Matthew C Oreilly, Paul G. Thomas, Sarah A Scott, Kyle A Brown, Thomas Oguin, Scott J Daniels, Ryan D Morrison, Alex H Brown, Craig W. LindsleyAbstract: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 ...
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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, 2013Co-Authors: Matthew C Oreilly, Paul G. Thomas, Sarah A Scott, Kyle A Brown, Thomas Oguin, Scott J Daniels, Ryan D Morrison, Alex H Brown, Craig W. LindsleyAbstract: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 that 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.
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fluorous tethered quenching reagents for solution phase Parallel Synthesis
Tetrahedron Letters, 2002Co-Authors: Craig W. Lindsley, Zhijian Zhao, William LeisterAbstract:Abstract Commercially available fluorous-tethered reagents are employed to quench excess reactants and remove known impurities from crude reaction mixtures generated via solution phase Parallel Synthesis. Fluorous quenching reagents are expediently removed via Fluoro Flash ™ SPE columns to afford products in high yields and purities.
Scott J Daniels - One of the best experts on this subject based on the ideXlab platform.
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discovery of r 2 fluoro 4 4 methoxyphenyl ethynyl phenyl 3 hydroxypiperidin 1 yl methanone ml337 an mglu3 selective and cns penetrant negative allosteric modulator nam
Journal of Medicinal Chemistry, 2013Co-Authors: Cody J Wenthur, Jeffrey P Conn, Scott J Daniels, Ryan D Morrison, Andrew S Felts, Katrina A Smith, Julie L Engers, Frank W Byers, Kyle A Emmitte, Craig W. LindsleyAbstract:A multidimensional, iterative Parallel Synthesis effort identified a series of highly selective mGlu3 NAMs with submicromolar potency and good CNS penetration. Of these, ML337 resulted (mGlu3 IC50 = 593 nM, mGlu2 IC50 >30 μM) with B:P ratios of 0.92 (mouse) to 0.3 (rat). DMPK profiling and shallow SAR led to the incorporation of deuterium atoms to address a metabolic soft spot, which subsequently lowered both in vitro and in vivo clearance by >50%.
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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, 2013Co-Authors: Matthew C Oreilly, Paul G. Thomas, Sarah A Scott, Kyle A Brown, Thomas Oguin, Scott J Daniels, Ryan D Morrison, Alex H Brown, Craig W. LindsleyAbstract: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 ...
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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, 2013Co-Authors: Matthew C Oreilly, Paul G. Thomas, Sarah A Scott, Kyle A Brown, Thomas Oguin, Scott J Daniels, Ryan D Morrison, Alex H Brown, Craig W. LindsleyAbstract: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 that 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.
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discovery and optimization of a novel selective and brain penetrant m1 positive allosteric modulator pam the development of ml169 an mlpcn probe
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Paul R Reid, Thomas M Bridges, Douglas J Sheffler, Hyekyung P Cho, Michelle L Lewis, Emily Days, Scott J DanielsAbstract: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.
Wei Zhang - One of the best experts on this subject based on the ideXlab platform.
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fluorous Parallel Synthesis of a piperazinedione fused tricyclic compound library
ACS Combinatorial Science, 2009Co-Authors: Stefan Werner, Simon D Nielsen, Peter Wipf, David M Turner, Peter G Chambers, Steven J Geib, Dennis P Curran, Wei ZhangAbstract:A fluorous-linker-assisted solution-phase protocol has been developed and applied to Parallel Synthesis of a piperazinedione-fused tricyclic compound library. The one-pot [3 + 2] cycloaddition of fluorous amino esters, aldehydes, and maleimides afforded bicyclic proline derivatives. The intermediates were subjected to N-acylation with chloroacetyl chloride, followed by displacement reactions with amines. Linker cleavage with concomitant lactamization yielded the final products. Microwave heating was employed to facilitate several reaction steps and fluorous solid phase extraction (F-SPE) was employed to purify the intermediates. During the method development, a small library containing sixteen analogs was prepared. The optimized conditions were applied to the Synthesis of a production library containing ninety analogs.
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solution phase Parallel Synthesis of an n alkylated dihydropteridinone library from fluorous amino acids
ACS Combinatorial Science, 2004Co-Authors: Tadamichi Nagashima, Wei ZhangAbstract:Parallel Synthesis of an N-alkylated dihydropteridinone library has been accomplished in five steps starting from two displacement reactions of 4,6-dichloro-5-nitropyrimidine, first with fluorous amino acids, then with secondary amines. The hydrogenation of the nitro group followed by microwave-assisted cyclization gave the dihydropteridinones. Further diversification was achieved by the reaction of dihydropteridinones with benzyl halides to afford mono-N-alkylated products. All the reaction intermediates and final products were purified by SPE or precipitation without the need to perform chromatography.
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fluorous electrophilic scavengers for solution phase Parallel Synthesis
Tetrahedron Letters, 2003Co-Authors: Wei Zhang, Christine Hiutung Chen, Tadamichi NagashimaAbstract:Abstract A fluorous isatoic anhydride and isocyanate are synthesized and used as scavengers for amines in solution-phase Parallel Synthesis of urea, thiourea, and β-hydroxyamine analogs. The resulting fluorous derivatives are readily separated from the reaction mixture by solid-phase extractions (SPE) over Fluoro Flash ™ cartridges to give products with good purity. The SPE cartridges can be reused.
Richard C. Larock - One of the best experts on this subject based on the ideXlab platform.
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Solution-phase Parallel Synthesis of a multisubstituted cyclic imidate library.
ACS combinatorial science, 2013Co-Authors: Saurabh Mehta, Jesse Waldo, Benjamin Neuenswander, Gerald H. Lushington, Richard C. LarockAbstract:The solution-phase Parallel Synthesis of a diverse 71-member library of multisubstituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki–Miyaura, Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of commercially available building blocks.
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Solution-Phase Parallel Synthesis of a Multisubstituted Cyclic Imidate Library
2013Co-Authors: Saurabh Mehta, Benjamin Neuenswander, Gerald H. Lushington, Jesse P. Waldo, Richard C. LarockAbstract:The solution-phase Parallel Synthesis of a diverse 71-member library of multisubstituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki–Miyaura, Sonogashira, carbonylative amidation, and Heck chemistry using sublibraries of commercially available building blocks
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solution phase Parallel Synthesis of a multi substituted benzo b thiophene library
ACS Combinatorial Science, 2009Co-Authors: Chulhee Cho, Benjamin Neuenswander, Gerald H. Lushington, Richard C. LarockAbstract:Generation of a library using Parallel syntheses of multi-substituted benzo[b]thiophenes is described. The requisite 3-iodobenzo[b]thiophenes are readily prepared in excellent yields from various alkynes bearing electron-rich aromatic rings by electrophilic cyclization using I2 in CH2Cl2. The heteroaromatic carbon−iodine bonds allow further diversification by palladium-catalyzed Suzuki−Miyaura, Sonogashira, Heck, and carboalkoxylation chemistry to give multi-substituted benzo[b]thiophene derivatives.
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solution phase Synthesis of a diverse library of highly substituted isoxazoles
ACS Combinatorial Science, 2008Co-Authors: Jesse Waldo, Saurabh Mehta, Benjamin Neuenswander, Gerald H. Lushington, Richard C. LarockAbstract:The iodocyclization of O-methyloximes of 2-alkyn-1-ones affords 4-iodoisoxazoles, which undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles. The palladium-catalyzed processes have been adapted to Parallel Synthesis utilizing commercially available boronic acid, acetylene, styrene, and amine sublibraries. Accordingly, a diverse 51-member library of 3,4,5-trisubstituted isoxazoles has been generated.
Matthew C Oreilly - One of the best experts on this subject based on the ideXlab platform.
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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, 2013Co-Authors: Matthew C Oreilly, Paul G. Thomas, Sarah A Scott, Kyle A Brown, Thomas Oguin, Scott J Daniels, Ryan D Morrison, Alex H Brown, Craig W. LindsleyAbstract: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 ...
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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, 2013Co-Authors: Matthew C Oreilly, Paul G. Thomas, Sarah A Scott, Kyle A Brown, Thomas Oguin, Scott J Daniels, Ryan D Morrison, Alex H Brown, Craig W. LindsleyAbstract: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 that 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.
