Delving into the Latest Updates on Phenserine tartrate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(-)-eseroline phenylcarbamate, (-)-phenserine, Phenserine

+ [1]

Target

AChE x amylin

Mechanism

AChE inhibitors(Acetylcholinesterase inhibitors), amylin inhibitors(Islet amyloid polypeptide inhibitors)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Alzheimer DiseasePoisoning

Originator Organization

Annovis Bio, Inc.

Active Organization-

Inactive Organization

Daewoong Pharmaceutical Co., Ltd.

Annovis Bio, Inc.Cenomed BioSciences LLC

Drug Highest PhaseDiscontinuedClinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC20H23N3O2

InChIKeyPBHFNBQPZCRWQP-QUCCMNQESA-N

CAS Registry101246-66-6

View All Structures (2)

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Ongoing research to develop AD treatments has characterized multiple drug targets including the cholinergic system, amyloid-β peptide, phosphorylated tau, and neuroinflammation. These systems have the potential to interact to either drive or slow AD progression. Promising agents that simultaneously impact many of these drug targets are the AD experimental drug Posiphen and its enantiomer phenserine that, currently, are separately being evaluated in clinical trials. To define the cholinergic component of these agents, the anticholinesterase activities of a ligand dataset comprising Posiphen and primary metabolites ((+)-N1-norPosiphen, (+)-N8-norPosiphen, and (+)-N1,N8-bisnorPosiphen) were characterized and compared to those of the enantiomer phenserine. The "target" dataset involved the human cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Binding interactions between the ligands and targets were analyzed using Autodock 4.2. The computationally determined inhibitory action of these ligands was then compared to ex vivo laboratory-measured values versus human AChE and BChE. While Posiphen lacked AChE inhibitory action, its major and minor metabolites (+)-N1-norPosiphen and (+)-N1,N8-bisnorPosiphen, respectively, possessed modest AChE inhibitory activity, and Posiphen and all metabolites lacked BChE action. Phenserine, as a positive control, demonstrated AChE-selective inhibitory action. In light of AChE inhibitory action deriving from a major and minor Posiphen metabolite, current Posiphen clinical trials in AD and related disorders should additionally evaluate AChE inhibition; particularly if Posiphen should be combined with a known anticholinesterase, since this drug class is clinically approved and the standard of care for AD subjects, and excessive AChE inhibition may impact drug tolerability.

20 Aug 2021·Organic LettersQ1 · CHEMISTRY

Mutasynthesis of Physostigmines in Myxococcus xanthus

Q1 · CHEMISTRY

Article

Author: Kaiser, Marcel ; Greven, Nico-Joel ; Nett, Markus ; Hiller, Wolf ; Pietruszka, Jörg ; Winand, Lea ; Schneider, Pascal ; Kruth, Sebastian

The alkaloid physostigmine is an approved anticholinergic drug and an important lead structure for the development of novel therapeutics. Using a complementary approach that merged chemical synthesis with pathway refactoring, we produced a series of physostigmine analogues with altered specificity and toxicity profiles in the heterologous host Myxococcus xanthus. The compounds that were generated by applying a simple feeding strategy include the promising drug candidate phenserine, which was previously accessible only by total synthesis.

01 Jun 2020·CNS Neuroscience & TherapeuticsQ2 · MEDICINE

(−)‐Phenserine tartrate (PhenT) as a treatment for traumatic brain injury

Q2 · MEDICINE

ReviewOA

Author: Hsueh, Shih‐Chang ; Glotfelty, Elliot J. ; Chiang, Yung‐Hsiao ; Hoffer, Barry J. ; Greig, Nigel H. ; Tweedie, David ; Becker, Robert E. ; Lecca, Daniela ; Nogueras‐Ortiz, Carlos ; Kapogiannis, Dimitrios

AbstractAimTraumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury‐associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI‐linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism‐targeted drug unlikely.DiscussionWe review recent data indicating that the small molecular weight drug (−)‐phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI‐ and modTBI‐induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury‐induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well‐characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman.ConclusionIn the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast‐tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

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