Literature DB >> 29754948

The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core.

Jeanette L Bertron1, Hyekyung P Cho2, Pedro M Garcia-Barrantes1, Joseph D Panarese2, James M Salovich2, Kellie D Nance2, Darren W Engers2, Jerri M Rook2, Anna L Blobaum2, Colleen M Niswender3, Shaun R Stauffer4, P Jeffrey Conn3, Craig W Lindsley5.   

Abstract

This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
Copyright © 2018 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  M(1); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Schizophrenia; Structure-Activity Relationship (SAR)

Mesh：

Substances：

Year:  2018        PMID： 29754948      PMCID： PMC6427922          DOI： 10.1016/j.bmcl.2018.05.009

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


  14 in total

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Authors:  Craig W Lindsley; Kyle A Emmitte; Corey R Hopkins; Thomas M Bridges; Karen J Gregory; Colleen M Niswender; P Jeffrey Conn
Journal:  Chem Rev       Date:  2016-02-16       Impact factor: 60.622

2.  Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery.

Authors:  Travis T Wager; Xinjun Hou; Patrick R Verhoest; Anabella Villalobos
Journal:  ACS Chem Neurosci       Date:  2016-04-04       Impact factor: 4.418

Review 3.  Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease.

Authors:  Bruce J Melancon; James C Tarr; Joseph D Panarese; Michael R Wood; Craig W Lindsley
Journal:  Drug Discov Today       Date:  2013-09-17       Impact factor: 7.851

4.  Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs.

Authors:  Jerri M Rook; Masahito Abe; Hyekyung P Cho; Kellie D Nance; Vincent B Luscombe; Jeffrey J Adams; Jonathan W Dickerson; Daniel H Remke; Pedro M Garcia-Barrantes; Darren W Engers; Julie L Engers; Sichen Chang; Jarrett J Foster; Anna L Blobaum; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2017-01-10       Impact factor: 4.418

5.  Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity.

Authors:  Jennifer E Davoren; Michelle Garnsey; Betty Pettersen; Michael A Brodney; Jeremy R Edgerton; Jean-Philippe Fortin; Sarah Grimwood; Anthony R Harris; Stephen Jenkinson; Terry Kenakin; John T Lazzaro; Che-Wah Lee; Susan M Lotarski; Lisa Nottebaum; Steven V O'Neil; Michael Popiolek; Simeon Ramsey; Stefanus J Steyn; Catherine A Thorn; Lei Zhang; Damien Webb
Journal:  J Med Chem       Date:  2017-07-26       Impact factor: 7.446

6.  Disease-Modifying Effects of M1 Muscarinic Acetylcholine Receptor Activation in an Alzheimer's Disease Mouse Model.

Authors:  Evan P Lebois; Jason P Schroeder; Thomas J Esparza; Thomas M Bridges; Craig W Lindsley; P Jeffrey Conn; David L Brody; J Scott Daniels; Allan I Levey
Journal:  ACS Chem Neurosci       Date:  2017-03-07       Impact factor: 4.418

7.  Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M(1) positive allosteric modulators.

Authors:  Feng V Yang; William D Shipe; Jaime L Bunda; M Brad Nolt; David D Wisnoski; Zhijian Zhao; James C Barrow; William J Ray; Lei Ma; Marion Wittmann; Matthew A Seager; Kenneth A Koeplinger; George D Hartman; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2009-11-24       Impact factor: 2.823

8.  A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning.

Authors:  Jana K Shirey; Ashley E Brady; Paulianda J Jones; Albert A Davis; Thomas M Bridges; J Phillip Kennedy; Satyawan B Jadhav; Usha N Menon; Zixiu Xiang; Mona L Watson; Edward P Christian; James J Doherty; Michael C Quirk; Dean H Snyder; James J Lah; Allan I Levey; Michelle M Nicolle; Craig W Lindsley; P Jeffrey Conn
Journal:  J Neurosci       Date:  2009-11-11       Impact factor: 6.167

Review 9.  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

10.  Design and optimization of selective azaindole amide M1 positive allosteric modulators.

Authors:  Jennifer E Davoren; Steven V O'Neil; Dennis P Anderson; Michael A Brodney; Lois Chenard; Keith Dlugolenski; Jeremy R Edgerton; Michael Green; Michelle Garnsey; Sarah Grimwood; Anthony R Harris; Gregory W Kauffman; Erik LaChapelle; John T Lazzaro; Che-Wah Lee; Susan M Lotarski; Deane M Nason; R Scott Obach; Veronica Reinhart; Romelia Salomon-Ferrer; Stefanus J Steyn; Damien Webb; Jiangli Yan; Lei Zhang
Journal:  Bioorg Med Chem Lett       Date:  2015-11-17       Impact factor: 2.823
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  5 in total

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Journal:  ACS Med Chem Lett       Date:  2022-04-19       Impact factor: 4.632

Review 2.  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

3.  Occurrence of Morpholine in Central Nervous System Drug Discovery.

Authors:  Elena Lenci; Lorenzo Calugi; Andrea Trabocchi
Journal:  ACS Chem Neurosci       Date:  2021-01-18       Impact factor: 4.418

4.  Chromone-Containing Allylmorpholines Influence Ion Channels in Lipid Membranes via Dipole Potential and Packing Stress.

Authors:  Svetlana S Efimova; Vera A Martynyuk; Anastasiia A Zakharova; Natalia M Yudintceva; Nikita M Chernov; Igor P Yakovlev; Olga S Ostroumova
Journal:  Int J Mol Sci       Date:  2022-09-30       Impact factor: 6.208

Review 5.  Multitargeting nature of muscarinic orthosteric agonists and antagonists.

Authors:  Jaromir Myslivecek
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  5 in total

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