Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice.
Bioorg Med Chem Lett
; 27(10): 2087-2093, 2017 05 15.
Article
em En
| MEDLINE
| ID: mdl-28389149
ABSTRACT
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.
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Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
/
Bloqueadores do Canal de Sódio Disparado por Voltagem
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article