Literature DB >> 27939174

Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.

Michael R Wood1, Meredith J Noetzel2, Michael S Poslusney3, Bruce J Melancon2, James C Tarr3, Atin Lamsal3, Sichen Chang3, Vincent B Luscombe2, Rebecca L Weiner2, Hyekyung P Cho2, Michael Bubser3, Carrie K Jones4, Colleen M Niswender4, Michael W Wood5, Darren W Engers2, Nicholas J Brandon5, Mark E Duggan5, P Jeffrey Conn4, Thomas M Bridges6, Craig W Lindsley7.   

Abstract

This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
Copyright © 2016 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-activity relationship (SAR)

Mesh：

Substances：

Year:  2016        PMID： 27939174      PMCID： PMC5340297          DOI： 10.1016/j.bmcl.2016.11.086

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


  18 in total

Review 1.  Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia.

Authors:  Carrie K Jones; Nellie Byun; Michael Bubser
Journal:  Neuropsychopharmacology       Date:  2011-09-28       Impact factor: 7.853

2.  Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4).

Authors:  Emery Smith; Peter Chase; Colleen M Niswender; Thomas J Utley; Douglas J Sheffler; Meredith J Noetzel; Atin Lamsal; Michael R Wood; P Jeffrey Conn; Craig W Lindsley; Franck Madoux; Mary Acosta; Louis Scampavia; Timothy Spicer; Peter Hodder
Journal:  J Biomol Screen       Date:  2015-04-15

3.  An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.

Authors:  Jana K Shirey; Zixiu Xiang; Darren Orton; Ashley E Brady; Kari A Johnson; Richard Williams; Jennifer E Ayala; Alice L Rodriguez; Jürgen Wess; David Weaver; Colleen M Niswender; P Jeffrey Conn
Journal:  Nat Chem Biol       Date:  2007-12-02       Impact factor: 15.040

4.  Allosteric antipsychotics: m4 muscarinic potentiators as novel treatments for schizophrenia.

Authors:  Martilias Farrell; Bryan L Roth
Journal:  Neuropsychopharmacology       Date:  2010-03       Impact factor: 7.853

5.  Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor.

Authors:  James M Salovich; Paige N Vinson; Douglas J Sheffler; Atin Lamsal; Thomas J Utley; Anna L Blobaum; Thomas M Bridges; Uyen Le; Carrie K Jones; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley; Corey R Hopkins
Journal:  Bioorg Med Chem Lett       Date:  2012-06-06       Impact factor: 2.823

6.  Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.

Authors:  Nellie E Byun; Michael Grannan; Michael Bubser; Robert L Barry; Analisa Thompson; John Rosanelli; Raajaram Gowrishankar; Nathaniel D Kelm; Stephen Damon; Thomas M Bridges; Bruce J Melancon; James C Tarr; John T Brogan; Malcolm J Avison; Ariel Y Deutch; Jürgen Wess; Michael R Wood; Craig W Lindsley; John C Gore; P Jeffrey Conn; Carrie K Jones
Journal:  Neuropsychopharmacology       Date:  2014-01-20       Impact factor: 7.853

7.  Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.

Authors:  Michael R Wood; Meredith J Noetzel; James C Tarr; Alice L Rodriguez; Atin Lamsal; Sichen Chang; Jarrett J Foster; Emery Smith; Peter Chase; Peter S Hodder; Darren W Engers; Colleen M Niswender; Nicholas J Brandon; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-07-21       Impact factor: 2.823

8.  Characterization of the novel positive allosteric modulator, LY2119620, at the muscarinic M(2) and M(4) receptors.

Authors:  Carrie H Croy; Douglas A Schober; Hongling Xiao; Anne Quets; Arthur Christopoulos; Christian C Felder
Journal:  Mol Pharmacol       Date:  2014-05-07       Impact factor: 4.436

9.  Synthesis and structure-activity relationships of allosteric potentiators of the m(4) muscarinic acetylcholine receptor.

Authors:  J Phillip Kennedy; Thomas M Bridges; Patrick R Gentry; John T Brogan; Alexander S Kane; Carrie K Jones; Ashley E Brady; Jana K Shirey; P Jeffrey Conn; Craig W Lindsley
Journal:  ChemMedChem       Date:  2009-10       Impact factor: 3.466

10.  Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

Authors:  Michael R Wood; Meredith J Noetzel; Julie L Engers; Katrina A Bollinger; Bruce J Melancon; James C Tarr; Changho Han; Mary West; Alison R Gregro; Atin Lamsal; Sichen Chang; Sonia Ajmera; Emery Smith; Peter Chase; Peter S Hodder; Michael Bubser; Carrie K Jones; Corey R Hopkins; Kyle A Emmitte; Colleen M Niswender; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-05-05       Impact factor: 2.823
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  12 in total

1.  Discovery of VU0467485/AZ13713945: An M4 PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.

Authors:  Michael R Wood; Meredith J Noetzel; Bruce J Melancon; Michael S Poslusney; Kellie D Nance; Miguel A Hurtado; Vincent B Luscombe; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Sichen Chang; Michael Bubser; Anna L Blobaum; Darren W Engers; Colleen M Niswender; Carrie K Jones; Nicholas J Brandon; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2016-12-16       Impact factor: 4.345

2.  Optimization of M4 positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology.

Authors:  Bruce J Melancon; Michael R Wood; Meredith J Noetzel; Kellie D Nance; Eileen M Engelberg; Changho Han; Atin Lamsal; Sichen Chang; Hyekyung P Cho; Frank W Byers; Michael Bubser; Carrie K Jones; Colleen M Niswender; Michael W Wood; Darren W Engers; Dedong Wu; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-04-13       Impact factor: 2.823

3.  Novel M4 positive allosteric modulators derived from questioning the role and impact of a presumed intramolecular hydrogen-bonding motif in β-amino carboxamide-harboring ligands.

Authors:  Michael S Poslusney; James M Salovich; Michael R Wood; Bruce J Melancon; Katrina A Bollinger; Vincent B Luscombe; Alice L Rodriguez; Darren W Engers; Thomas M Bridges; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2018-12-18       Impact factor: 2.823

4.  PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems.

Authors:  Sean P Moran; Hyekyung P Cho; James Maksymetz; Daniel H Remke; Ryan M Hanson; Colleen M Niswender; Craig W Lindsley; Jerri M Rook; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2018-04-25       Impact factor: 4.418

5.  Total RNA Sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target.

Authors:  Rocco G Gogliotti; Nicole M Fisher; Branden J Stansley; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn; Colleen M Niswender
Journal:  J Pharmacol Exp Ther       Date:  2018-03-09       Impact factor: 4.030

6.  Challenges in the development of an M4 PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.

Authors:  James C Tarr; Michael R Wood; Meredith J Noetzel; Jeanette L Bertron; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Frank W Byers; Sichen Chang; Hyekyung P Cho; Carrie K Jones; Colleen M Niswender; Michael W Wood; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-05-06       Impact factor: 2.823

7.  SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs.

Authors:  Trevor C Chopko; Changho Han; Alison R Gregro; Darren W Engers; Andrew S Felts; Mike S Poslusney; Katrina A Bollinger; Ryan D Morrison; Michael Bubser; Atin Lamsal; Vincent B Luscombe; Hyekyung P Cho; Nathalie C Schnetz-Boutaud; Alice L Rodriguez; Sichen Chang; J Scott Daniels; Donald F Stec; Colleen M Niswender; Carrie K Jones; Michael R Wood; Michael W Wood; Mark E Duggan; Nicholas J Brandon; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley; Bruce J Melancon
Journal:  Bioorg Med Chem Lett       Date:  2019-06-20       Impact factor: 2.823

Review 8.  Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia.

Authors:  Samantha E Yohn; P Jeffrey Conn
Journal:  Neuropharmacology       Date:  2017-09-09       Impact factor: 5.250

Review 9.  Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders.

Authors:  Sean P Moran; James Maksymetz; P Jeffrey Conn
Journal:  Trends Pharmacol Sci       Date:  2019-11-08       Impact factor: 14.819

Review 10.  Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.

Authors:  Eric A Wold; Jianping Chen; Kathryn A Cunningham; Jia Zhou
Journal:  J Med Chem       Date:  2018-08-28       Impact factor: 7.446
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