Literature DB >> 31668424

An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders.

Jacob D Porter1, Oscar Vivas2, C David Weaver3, Abdulmohsen Alsafran1, Elliot DiMilo4, Leggy A Arnold4, Eamonn J Dickson2, Chris Dockendorff5.   

Abstract

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC50 = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.
Copyright © 2019 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  DMP 543; JDP-107; Kv7 blocker; Schizophrenia; Voltage-gated potassium channel

Mesh：

Substances：

Year:  2019        PMID： 31668424      PMCID： PMC6858848          DOI： 10.1016/j.bmcl.2019.126681

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


  22 in total

1.  Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991.

Authors:  H S Wang; B S Brown; D McKinnon; I S Cohen
Journal:  Mol Pharmacol       Date:  2000-06       Impact factor: 4.436

2.  A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells.

Authors:  C David Weaver; David Harden; Steven I Dworetzky; Barbara Robertson; Ronald J Knox
Journal:  J Biomol Screen       Date:  2004-12

Review 3.  Clinical Trials and Therapeutic Rationale for Drug Repurposing in Schizophrenia.

Authors:  Santiago G Lago; Sabine Bahn
Journal:  ACS Chem Neurosci       Date:  2018-07-18       Impact factor: 4.418

4.  Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons.

Authors:  J A Lamas; A A Selyanko; D A Brown
Journal:  Eur J Neurosci       Date:  1997-03       Impact factor: 3.386

5.  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

6.  Efficient pyridinylmethyl functionalization: synthesis of 10, 10-Bis[(2-fluoro-4-pyridinyl)methyl]-9(10H)-anthracenone (DMP 543), an acetylcholine release enhancing agent.

Authors:  J A Pesti; G F Huhn; J Yin; Y Xing; J M Fortunak; R A Earl
Journal:  J Org Chem       Date:  2000-11-17       Impact factor: 4.354

Review 7.  Neural KCNQ (Kv7) channels.

Authors:  David A Brown; Gayle M Passmore
Journal:  Br J Pharmacol       Date:  2009-03-09       Impact factor: 8.739

Review 8.  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

9.  Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.

Authors:  M E Schnee; B S Brown
Journal:  J Pharmacol Exp Ther       Date:  1998-08       Impact factor: 4.030

10.  3-Substituted, 3-(4-pyridinylmethyl)-1,3-dihydro-1-phenyl-2H-indol-2-ones as acetylcholine release enhancers: synthesis and SAR.

Authors:  W W Wilkerson; A A Kergaye; S W Tam
Journal:  J Med Chem       Date:  1993-10-01       Impact factor: 7.446
View more
  1 in total

Review 1.  Chemical modulation of Kv7 potassium channels.

Authors:  Matteo Borgini; Pravat Mondal; Ruiting Liu; Peter Wipf
Journal:  RSC Med Chem       Date:  2021-01-14
  1 in total

北京卡尤迪生物科技股份有限公司 © 2022-2023.