Literature DB >> 28237763

Continued optimization of the M5 NAM ML375: Discovery of VU6008667, an M5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies.

Kevin M McGowan1, Kellie D Nance2, Hykeyung P Cho1, Thomas M Bridges1, P Jeffrey Conn1, Carrie K Jones1, Craig W Lindsley3.   

Abstract

This letter describes the continued optimization of M5 NAM ML375 (VU0483253). While a valuable in vivo tool compound, ML375has an excessively long elimination half-life in rat (t1/2=80h), which can be problematic in certain rodent addiction paradigms (e.g., reinstatement). Thus, we required an M5 NAM of comparable potency to ML375, but with a rat t1/2 of less than 4h. Steep SAR plagued this chemotype, and here we detail aniline replacements that offered some improvements over ML375, but failed to advance. Ultimately, incorporation of a single methyl group to the 9b-phenyl ring acted as a metabolic shunt, providing (S)-11 (VU6008667), an equipotent M5 NAM, with high CNS penetration, excellent selectivity versus M1-4 and the desired short half-life (t1/2=2.3h) in rat.
Copyright © 2017 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  CNS penetration; M(5); Muscarinic acetylcholine receptor; Pharmacokinetics; Structure-Activity Relationship (SAR)

Mesh：

Substances：

Year:  2017        PMID： 28237763      PMCID： PMC5508536          DOI： 10.1016/j.bmcl.2017.02.020

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


  10 in total

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Journal:  J Med Chem       Date:  2012-01-06       Impact factor: 7.446

Review 2.  Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

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

3.  Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice.

Authors:  Morgane Thomsen; David P D Woldbye; Gitta Wörtwein; Anders Fink-Jensen; Jürgen Wess; S Barak Caine
Journal:  J Neurosci       Date:  2005-09-07       Impact factor: 6.167

4.  Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.

Authors:  Haruto Kurata; Patrick R Gentry; Masaya Kokubo; Hyekyung P Cho; Thomas M Bridges; Colleen M Niswender; Frank W Byers; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2014-12-13       Impact factor: 2.823

Review 5.  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

6.  Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes.

Authors:  Alexander R Geanes; Hykeyung P Cho; Kellie D Nance; Kevin M McGowan; P Jeffrey Conn; Carrie K Jones; Jens Meiler; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-07-30       Impact factor: 2.823

7.  Role for M5 muscarinic acetylcholine receptors in cocaine addiction.

Authors:  Anders Fink-Jensen; Irina Fedorova; Gitta Wörtwein; David P D Woldbye; Thøger Rasmussen; Morgane Thomsen; Tom G Bolwig; Karen M Knitowski; David L McKinzie; Masahisa Yamada; Jürgen Wess; Anthony Basile
Journal:  J Neurosci Res       Date:  2003-10-01       Impact factor: 4.164

8.  Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe.

Authors:  Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Hyekyung P Cho; Emery Smith; Peter Chase; Peter S Hodder; Thomas J Utley; Anuruddha Rajapakse; Frank Byers; Colleen M Niswender; Ryan D Morrison; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley
Journal:  ChemMedChem       Date:  2014-04-01       Impact factor: 3.466

9.  Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia.

Authors:  Anthony S Basile; Irina Fedorova; Agustin Zapata; Xiaoguang Liu; Toni Shippenberg; Alokesh Duttaroy; Masahisa Yamada; Jurgen Wess
Journal:  Proc Natl Acad Sci U S A       Date:  2002-08-01       Impact factor: 11.205

10.  Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).

Authors:  Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Meredith J Noetzel; Hyekyung P Cho; Atin Lamsal; Emery Smith; Peter Chase; Peter S Hodder; Colleen M Niswender; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley; Michael R Wood
Journal:  J Med Chem       Date:  2014-09-03       Impact factor: 7.446
  10 in total
  4 in total

1.  Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold.

Authors:  Aaron M Bender; Hyekyung P Cho; Kellie D Nance; Kaelyn S Lingenfelter; Vincent B Luscombe; Patrick R Gentry; Karl Voigtritter; Alice E Berizzi; Patrick M Sexton; Christopher J Langmead; Arthur Christopoulos; Charles W Locuson; Thomas M Bridges; Sichen Chang; Jordan C O'Neill; Xiaoyan Zhan; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2018-04-26       Impact factor: 4.418

2.  Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats.

Authors:  Eric J Nunes; Laura E Rupprecht; Daniel J Foster; Craig W Lindsley; P Jeffrey Conn; Nii A Addy
Journal:  Neuropharmacology       Date:  2020-04-05       Impact factor: 5.250

Review 3.  Targeting muscarinic receptors to treat schizophrenia.

Authors:  Daniel J Foster; Zoey K Bryant; P Jeffrey Conn
Journal:  Behav Brain Res       Date:  2021-02-26       Impact factor: 3.332

4.  Unified Approach to Diverse Fused Fragments via Catalytic Dehydrative Cyclization.

Authors:  Ashley J Basson; Nathan R Halcovitch; Mark G McLaughlin
Journal:  Chemistry       Date:  2022-07-04       Impact factor: 5.020
  4 in total

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