Literature DB >> 27476142

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

Michael R Wood1, Meredith J Noetzel2, James C Tarr3, Alice L Rodriguez3, Atin Lamsal3, Sichen Chang3, Jarrett J Foster3, Emery Smith4, Peter Chase4, Peter S Hodder5, Darren W Engers2, Colleen M Niswender6, Nicholas J Brandon7, Michael W Wood7, Mark E Duggan7, P Jeffrey Conn6, Thomas M Bridges8, Craig W Lindsley9.   

Abstract

This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
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： 27476142      PMCID： PMC4987221          DOI： 10.1016/j.bmcl.2016.07.042

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


  25 in total

1.  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

2.  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

Review 3.  Carbonyl reduction pathways in drug metabolism.

Authors:  Petra Malátková; Vladimír Wsól
Journal:  Drug Metab Rev       Date:  2013-10-31       Impact factor: 4.518

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.  Synthesis and pharmacological evaluation of M4 muscarinic receptor positive allosteric modulators derived from VU10004.

Authors:  Tracey Huynh; Celine Valant; Ian T Crosby; Patrick M Sexton; Arthur Christopoulos; Ben Capuano
Journal:  ACS Chem Neurosci       Date:  2015-04-17       Impact factor: 4.418

6.  Chemical modification of the M(1) agonist VU0364572 reveals molecular switches in pharmacology and a bitopic binding mode.

Authors:  Gregory J Digby; Thomas J Utley; Atin Lamsal; Christian Sevel; Douglas J Sheffler; Evan P Lebois; Thomas M Bridges; Michael R Wood; Colleen M Niswender; Craig W Lindsley; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2012-09-09       Impact factor: 4.418

Review 7.  Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia.

Authors:  Mohammad M Khan
Journal:  CNS Drugs       Date:  2016-07       Impact factor: 5.749

Review 8.  Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders.

Authors:  P Jeffrey Conn; Craig W Lindsley; Jens Meiler; Colleen M Niswender
Journal:  Nat Rev Drug Discov       Date:  2014-09       Impact factor: 84.694

9.  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

Review 10.  Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

Authors:  P Jeffrey Conn; Arthur Christopoulos; Craig W Lindsley
Journal:  Nat Rev Drug Discov       Date:  2009-01       Impact factor: 84.694
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  6 in total

1.  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

2.  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

3.  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

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

Authors:  Michael R Wood; Meredith J Noetzel; Michael S Poslusney; Bruce J Melancon; James C Tarr; Atin Lamsal; Sichen Chang; Vincent B Luscombe; Rebecca L Weiner; Hyekyung P Cho; Michael Bubser; Carrie K Jones; Colleen M Niswender; Michael W Wood; Darren W Engers; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-11-30       Impact factor: 2.823

5.  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 6.  Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias.

Authors:  Emma T van der Westhuizen; K H Christopher Choy; Celine Valant; Simon McKenzie-Nickson; Sophie J Bradley; Andrew B Tobin; Patrick M Sexton; Arthur Christopoulos
Journal:  Front Pharmacol       Date:  2021-01-29       Impact factor: 5.810
  6 in total

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