P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders. This journal is

Original languageEnglish (US)
Pages (from-to)6716-6726
Number of pages11
JournalChemical Society Reviews
Volume43
Issue number19
DOIs
StatePublished - 2014

Fingerprint

Neurodegenerative diseases
Brain
Derivatives
Molecules
Pharmaceutical Preparations
Proteins
Rodentia
Drug Discovery
carbazole
Pharmaceutical Chemistry
Blood-Brain Barrier

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases. / Pieper, Andrew A.; McKnight, Steven L.; Ready, Joseph M.

In: Chemical Society Reviews, Vol. 43, No. 19, 2014, p. 6716-6726.

Research output: Contribution to journalArticle

@article{6eeb385add0643b2ba9c0750e9d906cc,
title = "P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases",
abstract = "A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders. This journal is",
author = "Pieper, {Andrew A.} and McKnight, {Steven L.} and Ready, {Joseph M.}",
year = "2014",
doi = "10.1039/c3cs60448a",
language = "English (US)",
volume = "43",
pages = "6716--6726",
journal = "Chemical Society Reviews",
issn = "0306-0012",
publisher = "Royal Society of Chemistry",
number = "19",

}

TY - JOUR

T1 - P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases

AU - Pieper, Andrew A.

AU - McKnight, Steven L.

AU - Ready, Joseph M.

PY - 2014

Y1 - 2014

N2 - A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders. This journal is

AB - A novel neuroprotective small molecule was discovered using a target-agnostic in vivo screen in living mice. This aminopropyl carbazole, named P7C3, is orally bioavailable, crosses the blood-brain barrier, and is non-toxic at doses several fold higher than the efficacious dose. The potency and drug-like properties of P7C3 were optimized through a medicinal chemistry campaign, providing analogues for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with immobilizing moieties may reveal the protein targets of the P7C3 class of neuroprotective compounds. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders. This journal is

UR - http://www.scopus.com/inward/record.url?scp=84903734074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903734074&partnerID=8YFLogxK

U2 - 10.1039/c3cs60448a

DO - 10.1039/c3cs60448a

M3 - Article

C2 - 24514864

AN - SCOPUS:84903734074

VL - 43

SP - 6716

EP - 6726

JO - Chemical Society Reviews

JF - Chemical Society Reviews

SN - 0306-0012

IS - 19

ER -