Design, synthesis and evaluation of alpha lipoic acid derivatives to treat multiple sclerosis-associated central neuropathic pain.
Bioorg Med Chem
; 69: 116889, 2022 09 01.
Article
en En
| MEDLINE
| ID: mdl-35779512
ABSTRACT
Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate with clinically used pain-killers and so there is a large unmet medical need for novel treatments for alleviating MS-CNP. Although (R)-alpha lipoic acid (ALA) evoked significant pain relief efficacy in a mouse model of multiple sclerosis-associated central neuropathic pain (MS-CNP), this dietary supplement has poor oral bioavailability due to low gastric stability. Eight ester prodrugs of the R enantiomer of ALA [(R)-ALA] were designed encompassing a range of biocompatible hydrophobic and hydrophilic features and synthesized in an effort to identify a prodrug candidate that was stable at gastric and upper gastrointestinal tract (GIT) pH, and that could be released (hydrolyzed by esterases) in the blood to (R)-ALA immediately after absorption into the portal vein (i.e., highly desirable features for pain relief development). These biocompatible hydrophobic and hydrophilic (R)-ALA pro-dugs underwent comprehensive preliminary screening to reveal PD-ALA4 HCl salt (10) as a promising candidate and PD-ALA 7 (8) could be a viable substitute, utilizing enzyme-free gastric and intestinal stability assessments, LogP evaluations, in vitro plasma stability and caco-2 cell monolayer permeability.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Profármacos
/
Ácido Tióctico
/
Esclerosis Múltiple
/
Neuralgia
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Australia