Guaifenesin Derivatives Promote Neurite Outgrowth and Protect Diabetic Mice from Neuropathy

In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neuri...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2013-06, Vol.56 (12), p.5071-5078
Main Authors: Hadimani, Mallinath B, Purohit, Meena K, Vanampally, Chandrashaker, Van der Ploeg, Randy, Arballo, Victor, Morrow, Dwane, Frizzi, Katie E, Calcutt, Nigel A, Fernyhough, Paul, Kotra, Lakshmi P
Format: Article
Language:English
Subjects:
Animals
Diabetic Neuropathies - pathology
Diabetic Neuropathies - prevention & control
Female
Guaifenesin - analogs & derivatives
Guaifenesin - metabolism
Guaifenesin - pharmacokinetics
Guaifenesin - pharmacology
Humans
Male
Mice
Microsomes, Liver - metabolism
Neurites - drug effects
Neurites - metabolism
Permeability
Rats
Stereoisomerism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its R-enantiomer (R)-1 carried the most biological activity, whereas the S-enantiomer (S)-1 was inactive. Focused structural variations to (R/S)-1 was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (R/S)-1 and (R)-1 partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (R)-1 and (S)-1 are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm400401y