Discovery of DS-1971a, a Potent, Selective NaV1.7 Inhibitor.
J Med Chem
; 63(18): 10204-10220, 2020 09 24.
Article
de En
| MEDLINE
| ID: mdl-32392056
ABSTRACT
A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Pyrazoles
/
Pyrimidines
/
Sulfonamides
/
Canal sodique voltage-dépendant NAV1.7
/
Bloqueurs de canaux sodiques voltage-dépendants
/
Hyperalgésie
/
Analgésiques
Limites:
Animals
/
Female
/
Humans
/
Male
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2020
Type de document:
Article
Pays d'affiliation:
Japon