Guaifenesin derivatives promote neurite outgrowth and protect diabetic mice from
Authors Hadimani MB, Purohit MK, Vanampally C, Van der Ploeg R, Arballo V, Morrow D,
Frizzi KE, Calcutt NA, Fernyhough P, Kotra LP
Submitted By Nigel Calcutt on 10/29/2013
Status Published
Journal Journal of medicinal chemistry
Year 2013
Date Published 6/27/2013
Volume : Pages 56 : 5071 - 5078
PubMed Reference 23758573
Abstract 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.

Investigators with authorship
Nigel CalcuttUniversity of California San Diego