Literature DB >> 28197318

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

Michael R Wood1, Meredith J Noetzel1, Bruce J Melancon1, Michael S Poslusney2, Kellie D Nance2, Miguel A Hurtado2, Vincent B Luscombe1, Rebecca L Weiner1, Alice L Rodriguez1, Atin Lamsal1, Sichen Chang1, Michael Bubser1, Anna L Blobaum1, Darren W Engers1, Colleen M Niswender3, Carrie K Jones3, Nicholas J Brandon4, Michael W Wood4, Mark E Duggan4, P Jeffrey Conn3, Thomas M Bridges1, Craig W Lindsley1.   

Abstract

Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.

Entities:  

Keywords:  Positive allosteric modulator (PAM); VU0467485; muscarinic acetylcholine receptor 4 (M4); schizophrenia

Year:  2016        PMID： 28197318      PMCID： PMC5304297          DOI： 10.1021/acsmedchemlett.6b00461

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  24 in total

Review 1.  Towards a muscarinic hypothesis of schizophrenia.

Authors:  T J Raedler; F P Bymaster; R Tandon; D Copolov; B Dean
Journal:  Mol Psychiatry       Date:  2006-12-05       Impact factor: 15.992

2.  Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

Authors:  N C Bodick; W W Offen; A I Levey; N R Cutler; S G Gauthier; A Satlin; H E Shannon; G D Tollefson; K Rasmussen; F P Bymaster; D J Hurley; W Z Potter; S M Paul
Journal:  Arch Neurol       Date:  1997-04

3.  Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model.

Authors:  A Ghoshal; J M Rook; J W Dickerson; G N Roop; R D Morrison; N Jalan-Sakrikar; A Lamsal; M J Noetzel; M S Poslusney; M R Wood; B J Melancon; S R Stauffer; Z Xiang; J S Daniels; C M Niswender; C K Jones; C W Lindsley; P J Conn
Journal:  Neuropsychopharmacology       Date:  2015-06-25       Impact factor: 7.853

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

Review 5.  Muscarinic receptor pharmacology and circuitry for the modulation of cognition.

Authors:  Michael Bubser; Nellie Byun; Michael R Wood; Carrie K Jones
Journal:  Handb Exp Pharmacol       Date:  2012

Review 6.  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

7.  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

8.  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

9.  Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia.

Authors:  Anantha Shekhar; William Z Potter; Jeffrey Lightfoot; John Lienemann; Sanjay Dubé; Craig Mallinckrodt; Frank P Bymaster; David L McKinzie; Christian C Felder
Journal:  Am J Psychiatry       Date:  2008-07-01       Impact factor: 18.112

Review 10.  Allosteric modulators for the treatment of schizophrenia: targeting glutamatergic networks.

Authors:  Frank S Menniti; Craig W Lindsley; P Jeffrey Conn; Jayvardhan Pandit; Panayiotis Zagouras; Robert A Volkmann
Journal:  Curr Top Med Chem       Date:  2013       Impact factor: 3.295
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  15 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.  Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.

Authors:  Julie L Engers; Katrina A Bollinger; Rebecca L Weiner; Alice L Rodriguez; Madeline F Long; Megan M Breiner; Sichen Chang; Sean R Bollinger; Michael Bubser; Carrie K Jones; Ryan D Morrison; Thomas M Bridges; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2017-08-15       Impact factor: 4.345

4.  Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping.

Authors:  Madeline F Long; Julie L Engers; Sichen Chang; Xiaoyan Zhan; Rebecca L Weiner; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Darren W Engers; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-10-09       Impact factor: 2.823

5.  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

Review 6.  The neurobiological basis for novel experimental therapeutics in dystonia.

Authors:  Anthony M Downs; Kaitlyn M Roman; Simone A Campbell; Antonio Pisani; Ellen J Hess; Paola Bonsi
Journal:  Neurobiol Dis       Date:  2019-07-04       Impact factor: 5.996

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

8.  Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2.

Authors:  Madeline F Long; Rory A Capstick; Paul K Spearing; Julie L Engers; Alison R Gregro; Sean R Bollinger; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Craig W Lindsley; Darren W Engers; Kayla J Temple
Journal:  Bioorg Med Chem Lett       Date:  2021-10-26       Impact factor: 2.823

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

Authors:  Blake R Bewley; Paul K Spearing; Rebecca L Weiner; Vincent B Luscombe; Xiaoyan Zhan; Sichen Chang; Hyekyung P Cho; Alice L Rodriguez; Colleen M Niswender; P Jeffrey Conn; Thomas M Bridges; Darren W Engers; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-08-20       Impact factor: 2.823

Review 10.  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
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