Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.
J Med Chem
; 59(17): 7901-14, 2016 09 08.
Article
em En
| MEDLINE
| ID: mdl-27502700
ABSTRACT
A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitroin vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
/
Receptores do Fator de Crescimento Derivado de Plaquetas
/
Niacinamida
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Remodelação das Vias Aéreas
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Remodelação Vascular
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Hipertensão Pulmonar
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article