Literature DB >> 28866269

Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core.

Blake R Bewley1, Paul K Spearing1, Rebecca L Weiner1, Vincent B Luscombe1, Xiaoyan Zhan1, Sichen Chang1, Hyekyung P Cho1, Alice L Rodriguez1, Colleen M Niswender2, P Jeffrey Conn2, Thomas M Bridges3, Darren W Engers4, Craig W Lindsley5.   

Abstract

This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp=5.3, Kp,uu=2.4; MDCK-MDR1 (P-gp) ER=1.1).
Copyright © 2017 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  M(4); Muscarinic acetylcholine receptor; Non-human primate (NHP); Positive allosteric modulator (PAM); Structure-activity relationship (SAR)

Mesh：

Substances：

Year:  2017        PMID： 28866269      PMCID： PMC5688877          DOI： 10.1016/j.bmcl.2017.08.043

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


  19 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.  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

3.  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

4.  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

5.  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

6.  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

7.  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

8.  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

9.  Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release.

Authors:  Daniel J Foster; Jermaine M Wilson; Daniel H Remke; M Suhaib Mahmood; M Jashim Uddin; Jürgen Wess; Sachin Patel; Lawrence J Marnett; Colleen M Niswender; Carrie K Jones; Zixiu Xiang; Craig W Lindsley; Jerri M Rook; P Jeffrey Conn
Journal:  Neuron       Date:  2016-09-08       Impact factor: 17.173

10.  Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256.

Authors:  Michael D Grannan; Catharine A Mielnik; Sean P Moran; Robert W Gould; Jacob Ball; Zhuoyan Lu; Michael Bubser; Amy J Ramsey; Masahito Abe; Hyekyung P Cho; Kellie D Nance; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Carrie K Jones
Journal:  ACS Chem Neurosci       Date:  2016-10-05       Impact factor: 4.418
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  4 in total

1.  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

2.  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 3.  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

4.  Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa.

Authors:  Rupesh Agarwal; Barbara A Bensing; Dehui Mi; Paige N Vinson; Jerome Baudry; Tina M Iverson; Jeremy C Smith
Journal:  Biochem J       Date:  2020-10-16       Impact factor: 3.766
  4 in total

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