Literature DB >> 34531947

Discovery of Investigational Drug CT1812, an Antagonist of the Sigma-2 Receptor Complex for Alzheimer's Disease.

Gilbert M Rishton1, Gary C Look1, Zhi-Jie Ni2, Jason Zhang2, Yingcai Wang2, Yaodong Huang2, Xiaodong Wu2, Nicholas J Izzo1, Kelsie M LaBarbera1, Colleen S Limegrover1, Courtney Rehak1, Raymond Yurko1, Susan M Catalano1.   

Abstract

An unbiased phenotypic neuronal assay was developed to measure the synaptotoxic effects of soluble Aβ oligomers. A collection of CNS druglike small molecules prepared by conditioned extraction was screened. Compounds that prevented and reversed synaptotoxic effects of Aβ oligomers in neurons were discovered to bind to the sigma-2 receptor complex. Select development compounds displaced receptor-bound Aβ oligomers, rescued synapses, and restored cognitive function in transgenic hAPP Swe/Ldn mice. Our first-in-class orally administered small molecule investigational drug 7 (CT1812) has been advanced to Phase II clinical studies for Alzheimer's disease.
© 2021 American Chemical Society.

Entities:  

Year:  2021        PMID： 34531947      PMCID： PMC8436239          DOI： 10.1021/acsmedchemlett.1c00048

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.632


  46 in total

1.  Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.

Authors:  Bitna Yi; James J Sahn; Pooneh Memar Ardestani; Andrew K Evans; Luisa L Scott; Jessica Z Chan; Sangeetha Iyer; Ashley Crisp; Gabriella Zuniga; Jonathan T Pierce; Stephen F Martin; Mehrdad Shamloo
Journal:  J Neurochem       Date:  2017-02       Impact factor: 5.372

Review 2.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

Authors:  Christian Haass; Dennis J Selkoe
Journal:  Nat Rev Mol Cell Biol       Date:  2007-02       Impact factor: 94.444

3.  Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice.

Authors:  James J Sahn; Galo L Mejia; Pradipta R Ray; Stephen F Martin; Theodore J Price
Journal:  ACS Chem Neurosci       Date:  2017-07-13       Impact factor: 4.418

4.  Synaptic targeting by A beta oligomers (ADDLS) as a basis for memory loss in early Alzheimer's disease.

Authors:  William L Klein
Journal:  Alzheimers Dement       Date:  2006-01       Impact factor: 21.566

5.  The case for soluble Aβ oligomers as a drug target in Alzheimer's disease.

Authors:  Franz Hefti; William F Goure; Jasna Jerecic; Kent S Iverson; Patricia A Walicke; Grant A Krafft
Journal:  Trends Pharmacol Sci       Date:  2013-04-10       Impact factor: 14.819

Review 6.  Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.

Authors:  Tanaji T Talele
Journal:  J Med Chem       Date:  2017-09-08       Impact factor: 7.446

7.  Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.

Authors:  Nicholas J Izzo; Jinbin Xu; Chenbo Zeng; Molly J Kirk; Kelsie Mozzoni; Colleen Silky; Courtney Rehak; Raymond Yurko; Gary Look; Gilbert Rishton; Hank Safferstein; Carlos Cruchaga; Alison Goate; Michael A Cahill; Ottavio Arancio; Robert H Mach; Rolf Craven; Elizabeth Head; Harry LeVine; Tara L Spires-Jones; Susan M Catalano
Journal:  PLoS One       Date:  2014-11-12       Impact factor: 3.240

8.  A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease.

Authors:  Michael Grundman; Roger Morgan; Jason D Lickliter; Lon S Schneider; Steven DeKosky; Nicholas J Izzo; Robert Guttendorf; Michelle Higgin; Julie Pribyl; Kelsie Mozzoni; Hank Safferstein; Susan M Catalano
Journal:  Alzheimers Dement (N Y)       Date:  2019-01-23

9.  Thy1-hAPP(Lond/Swe+) mouse model of Alzheimer's disease displays broad behavioral deficits in sensorimotor, cognitive and social function.

Authors:  Mehrdad Faizi; Patrick L Bader; Nay Saw; Thuy-Vi V Nguyen; Simret Beraki; Tony Wyss-Coray; Frank M Longo; Mehrdad Shamloo
Journal:  Brain Behav       Date:  2012-03       Impact factor: 2.708

Review 10.  The amyloid hypothesis of Alzheimer's disease at 25 years.

Authors:  Dennis J Selkoe; John Hardy
Journal:  EMBO Mol Med       Date:  2016-06-01       Impact factor: 12.137
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  1 in total

1.  Selectivity profile comparison for certain γ-butyrolactone and oxazolidinone-based ligands on a sigma 2 receptor over sigma 1: a molecular docking approach.

Authors:  Richie R Bhandare; Dilep Kumar Sigalapalli; Afzal B Shaik; Daniel J Canney; Benjamin E Blass
Journal:  RSC Adv       Date:  2022-07-11       Impact factor: 4.036
  1 in total

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