Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis.
J Med Chem
; 60(8): 3383-3404, 2017 04 27.
Article
em En
| MEDLINE
| ID: mdl-28398044
ABSTRACT
Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Pancreatite
/
Inibidores Enzimáticos
/
Quinurenina 3-Mono-Oxigenase
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido