Literature DB >> 31248774

SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel, CNS penetrant tricyclic M4 PAMs.

Trevor C Chopko1, Changho Han1, Alison R Gregro1, Darren W Engers2, Andrew S Felts2, Mike S Poslusney1, Katrina A Bollinger1, Ryan D Morrison1, Michael Bubser2, Atin Lamsal1, Vincent B Luscombe1, Hyekyung P Cho1, Nathalie C Schnetz-Boutaud2, Alice L Rodriguez2, Sichen Chang2, J Scott Daniels3, Donald F Stec4, Colleen M Niswender5, Carrie K Jones2, Michael R Wood2, Michael W Wood6, Mark E Duggan6, Nicholas J Brandon6, P Jeffrey Conn5, Thomas M Bridges2, Craig W Lindsley7, Bruce J Melancon8.   

Abstract

This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Copyright © 2019 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  Aldehyde oxidase (AO); M(4); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Structure-activity relationship (SAR)

Year:  2019        PMID： 31248774      PMCID： PMC6690795          DOI： 10.1016/j.bmcl.2019.06.032

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


  22 in total

1.  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

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

3.  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

4.  State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects.

Authors:  Robert W Gould; Michael T Nedelcovych; Xuewen Gong; Erica Tsai; Michael Bubser; Thomas M Bridges; Michael R Wood; Mark E Duggan; Nicholas J Brandon; John Dunlop; Michael W Wood; Magnus Ivarsson; Meredith J Noetzel; J Scott Daniels; Colleen M Niswender; Craig W Lindsley; P Jeffrey Conn; Carrie K Jones
Journal:  Neuropharmacology       Date:  2015-11-23       Impact factor: 5.250

5.  Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia.

Authors:  W Y Chan; D L McKinzie; S Bose; S N Mitchell; J M Witkin; R C Thompson; A Christopoulos; S Lazareno; N J M Birdsall; F P Bymaster; C C Felder
Journal:  Proc Natl Acad Sci U S A       Date:  2008-08-04       Impact factor: 11.205

6.  Synthesis and structure-activity relationships of allosteric potentiators of the m(4) muscarinic acetylcholine receptor.

Authors:  J Phillip Kennedy; Thomas M Bridges; Patrick R Gentry; John T Brogan; Alexander S Kane; Carrie K Jones; Ashley E Brady; Jana K Shirey; P Jeffrey Conn; Craig W Lindsley
Journal:  ChemMedChem       Date:  2009-10       Impact factor: 3.466

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.  Centrally active allosteric potentiators of the M4 muscarinic acetylcholine receptor reverse amphetamine-induced hyperlocomotor activity in rats.

Authors:  Ashley E Brady; Carrie K Jones; Thomas M Bridges; J Phillip Kennedy; Analisa D Thompson; Justin U Heiman; Micah L Breininger; Patrick R Gentry; Huiyong Yin; Satyawan B Jadhav; Jana K Shirey; P Jeffrey Conn; Craig W Lindsley
Journal:  J Pharmacol Exp Ther       Date:  2008-09-04       Impact factor: 4.030

9.  Discovery, Synthesis, and Preclinical Characterization of N-(3-Chloro-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (VU0418506), a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu4).

Authors:  Darren W Engers; Anna L Blobaum; Rocco D Gogliotti; Yiu-Yin Cheung; James M Salovich; Pedro M Garcia-Barrantes; J Scott Daniels; Ryan Morrison; Carrie K Jones; Matthew G Soars; Xiaoliang Zhuo; Jeremy Hurley; John E Macor; Joanne J Bronson; P Jeffrey Conn; Craig W Lindsley; Colleen M Niswender; Corey R Hopkins
Journal:  ACS Chem Neurosci       Date:  2016-05-03       Impact factor: 4.418

10.  Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents.

Authors:  Michael Bubser; Thomas M Bridges; Ditte Dencker; Robert W Gould; Michael Grannan; Meredith J Noetzel; Atin Lamsal; Colleen M Niswender; J Scott Daniels; Michael S Poslusney; Bruce J Melancon; James C Tarr; Frank W Byers; Jürgen Wess; Mark E Duggan; John Dunlop; Michael W Wood; Nicholas J Brandon; Michael R Wood; Craig W Lindsley; P Jeffrey Conn; Carrie K Jones
Journal:  ACS Chem Neurosci       Date:  2014-08-19       Impact factor: 4.418
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  1 in total

Review 1.  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
  1 in total

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