Craig Lindsley

Summary

Affiliation: Vanderbilt University
Country: USA

Publications

  1. ncbi request reprint Preclinical drug discovery research and training at Vanderbilt
    Craig W Lindsley
    Vanderbilt Institute of Chemical Biology Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA
    ACS Chem Biol 2:17-20. 2007
  2. ncbi request reprint A unique industrial - academic collaboration towards the next generation of schizophrenia therapeutics
    Gregor J Macdonald
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232 USA
    Curr Top Med Chem 14:304-12. 2014
  3. doi request reprint Drugs for allosteric sites on receptors
    Cody J Wenthur
    Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600 email
    Annu Rev Pharmacol Toxicol 54:165-84. 2014
  4. pmc Classics in chemical neuroscience: clozapine
    Cody J Wenthur
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232 6600, United States
    ACS Chem Neurosci 4:1018-25. 2013
  5. ncbi request reprint The PI3K/Akt pathway: recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors
    Craig W Lindsley
    VICB Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Department of Chemistry, Vanderbilt University, Nashville, TN 37232 USA
    Curr Cancer Drug Targets 8:7-18. 2008
  6. ncbi request reprint The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update
    Craig W Lindsley
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA
    Curr Top Med Chem 10:458-77. 2010
  7. pmc Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators
    Colleen M Niswender
    Department of Pharmacology, Vanderbilt University Medical Center, 802 Robinson Research Building, Nashville, TN 37232 6600, USA
    Bioorg Med Chem Lett 18:5626-30. 2008
  8. pmc Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists
    L Michelle Lewis
    Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 18:885-90. 2008
  9. pmc Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM
    Thomas M Bridges
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:558-62. 2010
  10. doi request reprint Allosteric modulation of kinases and GPCRs: design principles and structural diversity
    Jana A Lewis
    Department of Pharmacology and Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    Curr Opin Chem Biol 12:269-80. 2008

Collaborators

Detail Information

Publications89

  1. ncbi request reprint Preclinical drug discovery research and training at Vanderbilt
    Craig W Lindsley
    Vanderbilt Institute of Chemical Biology Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA
    ACS Chem Biol 2:17-20. 2007
  2. ncbi request reprint A unique industrial - academic collaboration towards the next generation of schizophrenia therapeutics
    Gregor J Macdonald
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232 USA
    Curr Top Med Chem 14:304-12. 2014
    ..In this article, we will discuss the science which drove our collaboration as well as some key lessons learned. ..
  3. doi request reprint Drugs for allosteric sites on receptors
    Cody J Wenthur
    Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600 email
    Annu Rev Pharmacol Toxicol 54:165-84. 2014
    ..As the field has matured, as described here, key principles and strategies have emerged for the design of ligands/drugs for allosteric sites. ..
  4. pmc Classics in chemical neuroscience: clozapine
    Cody J Wenthur
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232 6600, United States
    ACS Chem Neurosci 4:1018-25. 2013
    ....
  5. ncbi request reprint The PI3K/Akt pathway: recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors
    Craig W Lindsley
    VICB Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Department of Chemistry, Vanderbilt University, Nashville, TN 37232 USA
    Curr Cancer Drug Targets 8:7-18. 2008
    ..This review will discuss the PI3K/Akt/PTEN pathway, allosteric and ATP-competitive Akt kinase inhibitors, their biological evaluation and progress towards target validation...
  6. ncbi request reprint The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update
    Craig W Lindsley
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA
    Curr Top Med Chem 10:458-77. 2010
    ..Moreover, Merck just disclosed positive Phase I data with an oral allosteric Akt inhibitor (MK-2206)...
  7. pmc Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators
    Colleen M Niswender
    Department of Pharmacology, Vanderbilt University Medical Center, 802 Robinson Research Building, Nashville, TN 37232 6600, USA
    Bioorg Med Chem Lett 18:5626-30. 2008
    ..Despite tremendous therapeutic potential, Compound 7, VU0080421, and related congeners represent only a handful of mGluR4 positive allosteric modulators ever described...
  8. pmc Synthesis and SAR of selective muscarinic acetylcholine receptor subtype 1 (M1 mAChR) antagonists
    L Michelle Lewis
    Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 18:885-90. 2008
    ..Compounds in this series possess M1 antagonist IC(50)s in the 441nM-19microM range with 8- to >340-fold functional selectivity versus rM2-rM5...
  9. pmc Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM
    Thomas M Bridges
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:558-62. 2010
    ..An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS...
  10. doi request reprint Allosteric modulation of kinases and GPCRs: design principles and structural diversity
    Jana A Lewis
    Department of Pharmacology and Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    Curr Opin Chem Biol 12:269-80. 2008
    ..Here, we review recent developments in the design principles and structural diversity of allosteric ligands for kinases and GPCRs...
  11. pmc Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold
    Sameer Sharma
    Department of Pharmacology, Vanderbilt University Medical Center, 12415D MRBIV, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 18:4098-101. 2008
    ....
  12. doi request reprint G-protein-coupled receptors: from classical modes of modulation to allosteric mechanisms
    Thomas M Bridges
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, Tennessee 37232, USA
    ACS Chem Biol 3:530-41. 2008
    ..Here, we review the fundamental aspects of allosteric GPCR modulation by small-molecule ligands, with particular focus on the emerging position of positive allosteric modulators in modern drug discovery...
  13. pmc Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4
    Colleen M Niswender
    Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
    Mol Pharmacol 74:1345-58. 2008
    ..These exciting results provide continued support for mGluR4 as a therapeutic target in PD...
  14. pmc Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia
    P Jeffrey Conn
    Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN, USA
    Trends Pharmacol Sci 30:25-31. 2009
    ..These mGlu receptor-selective PAMs have properties needed for optimization as clinical candidates and have robust effects in animal models that predict efficacy in treatment of schizophrenia...
  15. pmc Synthesis and SAR of analogues of the M1 allosteric agonist TBPB. Part I: Exploration of alternative benzyl and privileged structure moieties
    Thomas M Bridges
    Department of Pharmacology, Vanderbilt University Medical Center, 802 Robinson Research Building, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 18:5439-42. 2008
    ..With slight structural changes, mAChR selectivity was maintained, but the degree of partial M1 agonism varied considerably...
  16. pmc Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity
    Joy E Marlo
    Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA
    Mol Pharmacol 75:577-88. 2009
    ..These data also suggest that structurally diverse M(1) potentiators may act by distinct mechanisms and differentially regulate receptor coupling to downstream signaling pathways...
  17. pmc Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
    P Jeffrey Conn
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Medical Center, 1215 Light Hall, Nashville, Tennessee 37232, USA
    Nat Rev Drug Discov 8:41-54. 2009
    ..These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders...
  18. pmc Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders
    P Jeffrey Conn
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Medical Center, Nashville, TN 37232, USA
    Trends Pharmacol Sci 30:148-55. 2009
    ....
  19. ncbi request reprint Recent progress in the discovery and development of negative allosteric modulators of mGluR5
    Craig W Lindsley
    Vanderbilt University, Medical Research Building IV, Nashville, TN 37232, USA
    Curr Opin Drug Discov Devel 12:446-57. 2009
    ..Progress in the clinical setting with mGluR5 NAMs has also resulted in important recent advances, including the completion of proof-of-concept studies...
  20. pmc Development of a selective small-molecule inhibitor of Kir1.1, the renal outer medullary potassium channel
    Gautam Bhave
    Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Mol Pharmacol 79:42-50. 2011
    ..1 and more than 65 other potential off-targets. VU591 seems to block the intracellular pore of the channel. The development of VU591 may enable studies to explore the viability of ROMK as a diuretic target...
  21. pmc mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease
    Corey R Hopkins
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232 36000, USA
    Future Med Chem 1:501-13. 2009
    ..It is anticipated that continued progress in this area will further our understanding of the potential of mGluR4 modulation as a novel symptomatic and potentially disease-modifying treatment for Parkinson's disease...
  22. pmc Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis
    Charlene M Dunaway
    Vanderbilt University School of Medicine, A 4323 MCN, 1161 21st Avenue South, Nashville, TN 37232 2363, USA
    Mol Cell Biol 31:404-16. 2011
    ..Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms...
  23. pmc Synthesis and SAR of N-(4-(4-alklylpiperazin-1-yl)phenyl)benzamides as muscarinic acetylcholine receptor subtype 1 (M1) anatgonists
    Nicole R Miller
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:2174-7. 2010
    ..Compounds in this series possess M(1) antagonist IC(50)s in the 350 nM to >10 microM range with varying degrees of functional selectivity versus M(2)-M(5)...
  24. ncbi request reprint Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors
    Craig W Lindsley
    VICB Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA
    Curr Top Med Chem 7:1349-63. 2007
    ..Compounds within these classes Akt inhibitors have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed...
  25. doi request reprint Schizophrenia: moving beyond monoamine antagonists
    P Jeffrey Conn
    Vanderbilt University, Department of Pharmacology, Nashville, TN 37232, USA
    Mol Interv 8:99-107. 2008
    ..Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes...
  26. pmc Synthesis and SAR of analogs of the M1 allosteric agonist TBPB. Part II: Amides, sulfonamides and ureas--the effect of capping the distal basic piperidine nitrogen
    Nicole R Miller
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 18:5443-7. 2008
    ..Despite the large change in basicity and topology, M1 selectivity was maintained...
  27. pmc A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduces seizures without impairing hippocampus-dependent learning
    Douglas J Sheffler
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Mol Pharmacol 76:356-68. 2009
    ....
  28. pmc Design, synthesis, and biological evaluation of halogenated N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: discovery of an isoform-selective small molecule phospholipase D2 inhibitor
    Robert R Lavieri
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Med Chem 53:6706-19. 2010
    ..Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree...
  29. pmc Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4)
    Richard Williams
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:4967-70. 2009
    ..The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041...
  30. pmc Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats
    Carrie K Jones
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Neurosci 28:10422-33. 2008
    ..Together, these data suggest that selective activation of M(1) may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease...
  31. doi request reprint The antipsychotic potential of muscarinic allosteric modulation
    Thomas M Bridges
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    Drug News Perspect 23:229-40. 2010
    ..These data suggest that selective allosteric activation of either M(1) or M(4) has antipsychotic potential through distinct, yet complimentary mechanisms...
  32. ncbi request reprint Recent progress in the development of mGluR4 positive allosteric modulators for the treatment of Parkinson's disease
    Craig W Lindsley
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN 37232, USA
    Curr Top Med Chem 9:949-63. 2009
    ..This review will focus on the explosion of novel mGluR4 PAMs reported in the past year and the further preclinical validation of mGluR4 activation as a potentially groundbreaking treatment for Parkinson's disease...
  33. pmc Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM
    Thomas M Bridges
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:1972-5. 2010
    ..An iterative library synthesis approach delivered a potent (M(1) EC(50)=830 nM) and highly selective M(1) PAM (>30 microM vs M(2)-M(5))...
  34. pmc Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity
    Jana A Lewis
    Department of Pharmacology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:1916-20. 2009
    ....
  35. pmc A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning
    Jana K Shirey
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6600, USA
    J Neurosci 29:14271-86. 2009
    ....
  36. pmc Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5
    Andrew S Felts
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:6623-6. 2009
    ..This Letter describes the SAR of this series and the profile of selected compounds in selectivity and radioligand binding assays...
  37. pmc Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity
    Robert Lavieri
    Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:2240-3. 2009
    ..Interestingly, SAR for this diverged from our earlier efforts, and dual PLD1/2 inhibitors were also discovered within this series...
  38. pmc Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins
    Thomas M Bridges
    Vanderbilt Program in Drug Discovery, Department of Pharmacology and Chemistry, Vanderbilt University Medical Center, Nashville, TN 37232 0697, USA
    J Med Chem 52:3445-8. 2009
    ..Subsequent optimization led to the discovery of VU0238429, which possessed an EC(50) of approximately 1.16 microM at M5 with >30-fold selectivity versus M1 and M3, with no M2 or M4 potentiator activity...
  39. pmc Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines
    Sameer Sharma
    Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Med Chem 52:4103-6. 2009
    ....
  40. pmc 3-Cyano-5-fluoro-N-arylbenzamides as negative allosteric modulators of mGlu(5): Identification of easily prepared tool compounds with CNS exposure in rats
    Andrew S Felts
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:4390-4. 2010
    ..Subsequent evaluation of two new compounds in pharmacokinetic studies using intraperitoneal dosing in rats demonstrated good exposure in both plasma and brain samples...
  41. pmc Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs)
    Darren W Engers
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
    J Med Chem 52:4115-8. 2009
    ..Compounds 9b and 9c showed submicromolar potency at both human and rat mGluR4. In addition, both 9b and 9c were shown to be centrally penetrant in rats using nontoxic vehicles, a major advance for the mGluR4 field...
  42. pmc Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS)
    Darren W Engers
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:5175-8. 2010
    ..An iterative parallel approach to these compounds culminated in the discovery of VU0364439 (11) which represents the most potent (19.8 nM) mGlu(4) PAM reported to date...
  43. pmc Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype
    Alice L Rodriguez
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:3209-13. 2009
    ..This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold...
  44. pmc Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity
    Alice L Rodriguez
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, TN 37232 0697, USA
    Mol Pharmacol 78:1105-23. 2010
    ..In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders...
  45. pmc mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning
    Jennifer E Ayala
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    Neuropsychopharmacology 34:2057-71. 2009
    ..Discovery of small molecules that enhance both LTP and LTD in an activity-appropriate manner shows a unique action on synaptic plasticity that may provide a novel approach for the treatment of impaired cognitive function...
  46. doi request reprint Application of combinatorial chemistry science on modern drug discovery
    J Phillip Kennedy
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Comb Chem 10:345-54. 2008
  47. pmc Synthesis, SAR and unanticipated pharmacological profiles of analogues of the mGluR5 ago-potentiator ADX-47273
    Darren W Engers
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    ChemMedChem 4:505-11. 2009
    ..The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9-fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties...
  48. pmc Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness
    Sarah A Scott
    Department of Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, 2220 Pierce Avenue South, Nashville, Tennessee 37232 6600, USA
    Nat Chem Biol 5:108-17. 2009
    ....
  49. pmc In vivo structure-activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors
    Jijun Hao
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    ACS Chem Biol 5:245-53. 2010
    ....
  50. pmc Insulin reveals Akt signaling as a novel regulator of norepinephrine transporter trafficking and norepinephrine homeostasis
    Sabrina D Robertson
    Departments of Molecular Physiology and Biophysics, Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Neurosci 30:11305-16. 2010
    ..Furthermore, they provide one potential molecular mechanism by which Akt, a candidate gene for mood disorders such as schizophrenia and depression, can impact brain monoamine homeostasis...
  51. pmc Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats
    Ashley E Brady
    Department of Pharmacology, Vanderbilt Program in Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    J Pharmacol Exp Ther 327:941-53. 2008
    ....
  52. doi request reprint Total synthesis and biological evaluation of the marine bromopyrrole alkaloid dispyrin: elucidation of discrete molecular targets with therapeutic potential
    J Phillip Kennedy
    Department of Chemistry, Vanderbilt Program in Drug Discovery, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Vanderbilt Medical Center, Nashville, TN 37232 6600, USA
    J Nat Prod 71:1783-6. 2008
    ....
  53. pmc Synthesis and SAR of novel, non-MPEP chemotype mGluR5 NAMs identified by functional HTS
    Ya Zhou
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:6502-6. 2009
    ..This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and further examples of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold...
  54. ncbi request reprint Design of potent GlyT1 inhibitors: in vitro and in vivo profiles
    Thomas M Bridges
    Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    Curr Opin Mol Ther 10:591-601. 2008
    ..To date, a number of small-molecule GlyT1 inhibitors have been reported by the pharmaceutical industry. Developments in the discovery and characterization of GlyT1 inhibitors are discussed in this review...
  55. pmc Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells
    Todd W Miller
    Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
    Clin Cancer Res 15:7266-76. 2009
    ..Therefore, we examined whether mTOR inhibitors synergize with trastuzumab...
  56. ncbi request reprint The evolution of histamine H₃ antagonists/inverse agonists
    Evan P Lebois
    Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
    Curr Top Med Chem 11:648-60. 2011
    ..Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists...
  57. doi request reprint Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape
    Margrith E Mattmann
    Vanderbilt University, Vanderbilt Medical Center, Vanderbilt Program in Drug Discovery, Department of Pharmacology, Department of Chemistry, Nashville, TN 37232, USA
    Expert Opin Ther Pat 21:1309-38. 2011
    ..Both preclinical animal studies and clinical trials in humans have validated Akt as an important target of cancer drug discovery...
  58. ncbi request reprint Discovery and development of a potent and highly selective small molecule muscarinic acetylcholine receptor subtype I (mAChR 1 or M1) antagonist in vitro and in vivo probe
    C David Weaver
    The Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Nashville, TN 37232 USA
    Curr Top Med Chem 9:1217-26. 2009
    ..48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/ MLPCN probe molecule for studying and dissecting M(1) function...
  59. doi request reprint Progress toward the total synthesis of lucentamycin A: total synthesis and biological evaluation of 8-epi-lucentamycin A
    R Nathan Daniels
    Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, USA
    J Org Chem 74:8852-5. 2009
    ..2% overall yield. The key epi-nonproteogenic 3-methyl-4-ethylideneproline was synthesized via a titanium-mediated cycloisomerization reaction...
  60. pmc Dysregulation of the norepinephrine transporter sustains cortical hypodopaminergia and schizophrenia-like behaviors in neuronal rictor null mice
    Michael A Siuta
    Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    PLoS Biol 8:e1000393. 2010
    ..Additionally, our findings identify Akt as a novel modulator of monoamine homeostasis in the cortex...
  61. doi request reprint A novel class of H3 antagonists derived from the natural product guided synthesis of unnatural analogs of the marine bromopyrrole alkaloid dispyrin
    J Phillip Kennedy
    Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 19:3204-8. 2009
    ..Multiple rounds of iterative parallel synthesis improved human H(3) IC(50) approximately 33-fold, and afforded a new class of H(3) antagonists based on the novel bromotyramine core of dispyrin...
  62. pmc Small-molecule screen identifies inhibitors of the neuronal K-Cl cotransporter KCC2
    Eric Delpire
    Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Proc Natl Acad Sci U S A 106:5383-8. 2009
    ..We also used one of the compounds to demonstrate competitive inhibition in regard to external [K(+)] versus noncompetitive inhibition in respect to external [Cl(-)]...
  63. pmc A new multi-gram synthetic route to labeling precursors for the D(2/3) PET agent 18F-fallypride
    Kwangho Kim
    Department of Chemistry and Pharmacology, Institute of Chemical Biology, Vanderbilt University, 802 Robinson Research Building, Nashville, TN 37235 1822, USA
    Bioorg Med Chem Lett 18:4467-9. 2008
    ..In the course of our studies, we also discovered two novel labeling precusors, the previously undescribed mesylate and chloro congeners of fallypride...
  64. ncbi request reprint Molecule of the month
    Craig W Lindsley
    Department of Pharmacology, Vanderbilt University, Vanderbilt University Medical Center, Nashville, TN 37232 6600, USA
    Curr Top Med Chem 8:1100. 2008
  65. doi request reprint Total synthesis and biological evaluation of tambjamine K and a library of unnatural analogs
    Leslie N Aldrich
    Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
    Bioorg Med Chem Lett 20:5207-11. 2010
    ..Unnatural analogs were shown to be more potent in viability, proliferation, and invasion assays than the natural product in multiple cancer cell lines, with minimal to no cytotoxicity on non-transformed cell lines...
  66. ncbi request reprint Molecule of the month. Overcoming resistance
    Ashley L Thomas
    Vanderbilt University Medical Center, Department of Pharmacology and Chemistry, Robinson Research Buliding 804, Nashville, TN 37232 6600, USA
    Curr Top Med Chem 8:62. 2008
  67. ncbi request reprint Discovery of positive allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5)
    David L Williams
    Department of Imaging Research, Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486, USA
    Curr Top Med Chem 5:825-46. 2005
    ..Evaluation of assay data in mathematical models of allosterism to constrain possible mechanisms of action is briefly discussed. Other reviews of this emerging field with different emphases have been published recently [1-3]...
  68. ncbi request reprint Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors
    Craig W Lindsley
    Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486, USA
    Bioorg Med Chem Lett 15:761-4. 2005
    ..An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo...
  69. ncbi request reprint Discovery of positive allosteric modulators for the metabotropic glutamate receptor subtype 5 from a series of N-(1,3-diphenyl-1H- pyrazol-5-yl)benzamides that potentiate receptor function in vivo
    Craig W Lindsley
    Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Department of Neuroscience, Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
    J Med Chem 47:5825-8. 2004
    ..Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia...
  70. ncbi request reprint A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain
    Julie A O'Brien
    Neuroscience WP, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
    J Pharmacol Exp Ther 309:568-77. 2004
    ..These results demonstrate that allosteric potentiation of mGluR5 increases the effect of threshold agonist concentrations in native systems...
  71. ncbi request reprint Difference in mGluR5 interaction between positive allosteric modulators from two structural classes
    David L Williams
    Department of Neuroscience WP, Merck Research Laboratories, West Point, Pennsylvania and Rahway, New Jersey
    Ann N Y Acad Sci 1003:481-4. 2003
  72. ncbi request reprint A family of highly selective allosteric modulators of the metabotropic glutamate receptor subtype 5
    Julie A O'Brien
    Neuroscience WP46 300, Merck Research Laboratories, West Point, PA 19486, USA
    Mol Pharmacol 64:731-40. 2003
    ....
  73. ncbi request reprint Challenges in the development of mGluR5 positive allosteric modulators: the discovery of CPPHA
    Zhijian Zhao
    Department of Medicinal Chemistry, Merck and Co, Inc, PO Box 4, West Point, PA 19486, USA
    Bioorg Med Chem Lett 17:1386-91. 2007
    ..Binding to a unique allosteric binding site distinct from other mGluR5 PAMs, CPPHA has been the focus of numerous pharmacology studies by several laboratories...
  74. ncbi request reprint Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides
    Kausik K Nanda
    Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co, Inc, PO Box 4, West Point, PA 19486, USA
    Bioorg Med Chem Lett 16:5897-901. 2006
    ..Key compound 1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea (10) exhibits significant atrial-selective effects in an in vivo model...
  75. doi request reprint Discovery of 1,4-substituted piperidines as potent and selective inhibitors of T-type calcium channels
    Zhi Qiang Yang
    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA
    J Med Chem 51:6471-7. 2008
    ..Compound 30 thus demonstrates a wide margin between CNS and peripheral effects and is a useful tool for probing the effects of T-type calcium channel inhibition...
  76. ncbi request reprint Mastering medicinal chemistry: strategies, issues and success stories
    Craig W Lindsley
    Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486, USA
    Drug Discov Today 9:695-6. 2004
  77. doi request reprint Design, synthesis, and evaluation of a novel 4-aminomethyl-4-fluoropiperidine as a T-type Ca2+ channel antagonist
    William D Shipe
    Department of Medicinal Chemistry, Merck Research Laboratories, WP14 1, P O Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, USA
    J Med Chem 51:3692-5. 2008
    ..Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects...
  78. ncbi request reprint A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models
    Gene G Kinney
    Neuroscience West Point, Merck Research Laboratories, West Point, PA 19486, USA
    J Pharmacol Exp Ther 313:199-206. 2005
    ..These effects are consistent with the hypothesis that allosteric potentiation of mGluR5 may provide a novel approach for development of antipsychotic agents...
  79. ncbi request reprint Discovery of 2,3,5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors
    Zhijian Zhao
    Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486, USA
    Bioorg Med Chem Lett 15:905-9. 2005
    ..Compounds from this series, which contain a 5-tetrazolyl moiety, exhibit more potent inhibition of Akt2 than Akt1...
  80. ncbi request reprint Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members
    Deborah Defeo-Jones
    Department of Cancer Research, Merck Research Laboratories, Building 26 462, West Point, PA 19486, USA
    Mol Cancer Ther 4:271-9. 2005
    ..Finally, we show that inhibition of both Akt1 and Akt2 selectively sensitizes tumor cells, but not normal cells, to apoptotic stimuli...
  81. ncbi request reprint The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation
    Stanley F Barnett
    Department of Cancer Research, Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486 USA
    Curr Top Med Chem 5:109-25. 2005
    ..Inhibitors in this class may have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed...
  82. ncbi request reprint Recent advances in positive allosteric modulators of metabotropic glutamate receptors
    William D Shipe
    Merck Research Laboratories, Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Imaging Research, PO Box 4, WP14 1, Sumneytown Pike, West Point, PA 19486, USA
    Curr Opin Drug Discov Devel 8:449-57. 2005
    ..Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce the liability of receptor desensitization...
  83. ncbi request reprint Small molecule protein-protein inhibitors for the p53-MDM2 interaction
    Anna S Dudkina
    Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486, USA
    Curr Top Med Chem 7:952-60. 2007
    ..This review will detail the biology of the p53-MDM2 interaction, the major classes of SMPPIs and key medicinal chemistry and in vitro/in vivo biological data reported through October 2006...
  84. ncbi request reprint Targeting the phosphatidylinositol-3 kinase/Akt pathway for the treatment of cancer
    Donghwa Kim
    University of South Florida College of Medicine, Departments of Pathology and Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
    Curr Opin Investig Drugs 6:1250-8. 2005
    ..This review focuses on ongoing translational efforts to therapeutically target the PI3K/Akt pathway...
  85. ncbi request reprint Synthesis and SAR of novel histamine H3 receptor antagonists
    Cynthia D Jesudason
    Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
    Bioorg Med Chem Lett 16:3415-8. 2006
    ..The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H(3) receptors are reported...
  86. ncbi request reprint Synthesis and SAR of GlyT1 inhibitors derived from a series of N-((4-(morpholine-4-carbonyl)-1-(propylsulfonyl)piperidin-4-yl)methyl)benzamides
    Zhijian Zhao
    Department of Medicinal Chemistry, Merck and Co, Inc, PO Box 4, West Point, PA 19486, USA
    Bioorg Med Chem Lett 16:5968-72. 2006
    ..This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of potent and selective non-sarcosine-derived GlyT1 inhibitors...
  87. ncbi request reprint Identification of potent agonists of photoreceptor-specific nuclear receptor (NR2E3) and preparation of a radioligand
    Scott E Wolkenberg
    Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck and Co, Inc, PO Box 4, West Point, PA 19486, USA
    Bioorg Med Chem Lett 16:5001-4. 2006
    ..Agonists of NR2E3 (PNR, RNR) have been identified and optimized to EC(50)< 200 nM. A tritiated analogue of one agonist was prepared to aid in the development of a binding assay...
  88. ncbi request reprint Design, synthesis, and in vivo efficacy of glycine transporter-1 (GlyT1) inhibitors derived from a series of [4-phenyl-1-(propylsulfonyl)piperidin-4-yl]methyl benzamides
    Craig W Lindsley
    Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, P O Box 4, West Point, PA 19486, USA
    ChemMedChem 1:807-11. 2006
  89. ncbi request reprint Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia
    Craig W Lindsley
    Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co, PO Box 4, West Point, PA 19486, USA
    Curr Top Med Chem 6:771-85. 2006
    ..Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly...

Research Grants6

  1. Selective M1 mAChR allosteric modulators for the treatment of schizophrenia
    Craig Lindsley; Fiscal Year: 2010
    ....
  2. Partial Antagonists of mGluR5 for Treatment of Cocaine Addiction
    Craig Lindsley; Fiscal Year: 2010
    ..Our goal for this project is to develop a partial mGluR5 antagonist with an acceptable profile for preclinical and ultimately clinical development that may become a new drug to treat addictive disorders. ..