Literature DB >> 19097893

Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead.

Richard Williams1, Colleen M Niswender, Qingwei Luo, Uyen Le, P Jeffrey Conn, Craig W Lindsley.   

Abstract

This Letter describes the synthesis and SAR of two mGluR4 positive allosteric modulator leads, 6 and 7. VU001171 (6) represents the most potent (EC(50)=650 nM), efficacious (141% Glu Max) and largest fold shift (36-fold) of any mGluR4 PAM reported to date. However, this work highlights the challenges in hit-to-lead for mGluR4 PAMs, with multiple confirmed HTS hits displaying little or no tractable SAR.

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Year:  2008        PMID： 19097893      PMCID： PMC3787871          DOI： 10.1016/j.bmcl.2008.11.104

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  20 in total

Review 1.  Pharmacological agents acting at subtypes of metabotropic glutamate receptors.

Authors:  D D Schoepp; D E Jane; J A Monn
Journal:  Neuropharmacology       Date:  1999-10       Impact factor: 5.250

Review 2.  Pharmacology and functions of metabotropic glutamate receptors.

Authors:  P J Conn; J P Pin
Journal:  Annu Rev Pharmacol Toxicol       Date:  1997       Impact factor: 13.820

3.  (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist, is anticonvulsive and neuroprotective in vivo.

Authors:  F Gasparini; V Bruno; G Battaglia; S Lukic; T Leonhardt; W Inderbitzin; D Laurie; B Sommer; M A Varney; S D Hess; E C Johnson; R Kuhn; S Urwyler; D Sauer; C Portet; M Schmutz; F Nicoletti; P J Flor
Journal:  J Pharmacol Exp Ther       Date:  1999-06       Impact factor: 4.030

4.  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.

Authors:  Craig W Lindsley; David D Wisnoski; William H Leister; Julie A O'brien; Wei Lemaire; David L Williams; Maryann Burno; Cyrille Sur; Gene G Kinney; Doug J Pettibone; Philip R Tiller; Sheri Smith; Mark E Duggan; George D Hartman; P Jeffrey Conn; Joel R Huff
Journal:  J Med Chem       Date:  2004-11-18       Impact factor: 7.446

5.  Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson's disease treatment.

Authors:  Michael J Marino; David L Williams; Julie A O'Brien; Ornella Valenti; Terrence P McDonald; Michelle K Clements; Ruiping Wang; Anthony G DiLella; J Fred Hess; Gene G Kinney; P Jeffrey Conn
Journal:  Proc Natl Acad Sci U S A       Date:  2003-10-30       Impact factor: 11.205

6.  (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection.

Authors:  M Maj; V Bruno; Z Dragic; R Yamamoto; G Battaglia; W Inderbitzin; N Stoehr; T Stein; F Gasparini; I Vranesic; R Kuhn; F Nicoletti; P J Flor
Journal:  Neuropharmacology       Date:  2003-12       Impact factor: 5.250

7.  A novel selective allosteric modulator potentiates the activity of native metabotropic glutamate receptor subtype 5 in rat forebrain.

Authors:  Julie A O'Brien; Wei Lemaire; Marion Wittmann; Marlene A Jacobson; Sookhee N Ha; David D Wisnoski; Craig W Lindsley; Hervé J Schaffhauser; Blake Rowe; Cyrille Sur; Mark E Duggan; Douglas J Pettibone; P Jeffrey Conn; David L Williams
Journal:  J Pharmacol Exp Ther       Date:  2004-01-27       Impact factor: 4.030

8.  Anxiolytic-like effects of PHCCC, an allosteric modulator of mGlu4 receptors, in rats.

Authors:  Katarzyna Stachowicz; Kinga Kłak; Aleksandra Kłodzińska; Ewa Chojnacka-Wojcik; Andrzej Pilc
Journal:  Eur J Pharmacol       Date:  2004-09-13       Impact factor: 4.432

9.  L-2-amino-4-phosphonobutyrate (L-AP4) is an agonist at the type IV metabotropic glutamate receptor which is negatively coupled to adenylate cyclase.

Authors:  C Thomsen; P Kristensen; E Mulvihill; B Haldeman; P D Suzdak
Journal:  Eur J Pharmacol       Date:  1992-11-02       Impact factor: 4.432

10.  PHCCC, a specific enhancer of type 4 metabotropic glutamate receptors, reduces proliferation and promotes differentiation of cerebellar granule cell neuroprecursors.

Authors:  A M Canudas; V Di Giorgi-Gerevini; L Iacovelli; G Nano; M D'Onofrio; A Arcella; F Giangaspero; C Busceti; L Ricci-Vitiani; G Battaglia; F Nicoletti; D Melchiorri
Journal:  J Neurosci       Date:  2004-11-17       Impact factor: 6.167
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  13 in total

1.  Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.

Authors:  Bruce J Melancon; Corey R Hopkins; Michael R Wood; Kyle A Emmitte; Colleen M Niswender; Arthur Christopoulos; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2012-01-06       Impact factor: 7.446

2.  Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease.

Authors:  Matthew J Betts; Michael J O'Neill; Susan Duty
Journal:  Br J Pharmacol       Date:  2012-08       Impact factor: 8.739

3.  Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model.

Authors:  Carrie K Jones; Darren W Engers; Analisa D Thompson; Julie R Field; Anna L Blobaum; Stacey R Lindsley; Ya Zhou; Rocco D Gogliotti; Satyawan Jadhav; Rocio Zamorano; Jim Bogenpohl; Yoland Smith; Ryan Morrison; J Scott Daniels; C David Weaver; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins
Journal:  J Med Chem       Date:  2011-10-19       Impact factor: 7.446

4.  Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators.

Authors:  Ralf Mueller; Eric S Dawson; Colleen M Niswender; Mariusz Butkiewicz; Corey R Hopkins; C David Weaver; Craig W Lindsley; P Jeffrey Conn; Jens Meiler
Journal:  J Mol Model       Date:  2012-05-17       Impact factor: 1.810

Review 5.  Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.

Authors:  Albert J Robichaud; Darren W Engers; Craig W Lindsley; Corey R Hopkins
Journal:  ACS Chem Neurosci       Date:  2011-06-14       Impact factor: 4.418

6.  Solution-phase parallel synthesis and SAR of homopiperazinyl analogs as positive allosteric modulators of mGlu₄.

Authors:  Yiu-Yin Cheung; Rocio Zamorano; Anna L Blobaum; C David Weaver; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins
Journal:  ACS Comb Sci       Date:  2011-02-21       Impact factor: 3.784

Review 7.  mGluR4-positive allosteric modulation as potential treatment for Parkinson's disease.

Authors:  Corey R Hopkins; Craig W Lindsley; Colleen M Niswender
Journal:  Future Med Chem       Date:  2009-06       Impact factor: 3.808

Review 8.  Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease.

Authors:  Susan Duty
Journal:  Br J Pharmacol       Date:  2010-09       Impact factor: 8.739

9.  Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4).

Authors:  Richard Williams; Kari A Johnson; Patrick R Gentry; Colleen M Niswender; Charles D Weaver; P Jeffrey Conn; Craig W Lindsley; Corey R Hopkins
Journal:  Bioorg Med Chem Lett       Date:  2009-07-18       Impact factor: 2.823

10.  Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs).

Authors:  Darren W Engers; Colleen M Niswender; C David Weaver; Satyawan Jadhav; Usha N Menon; Rocio Zamorano; P Jeffrey Conn; Craig W Lindsley; Corey R Hopkins
Journal:  J Med Chem       Date:  2009-07-23       Impact factor: 7.446
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