4 research outputs found
Optimization of PDGFR inhibitors for duration of action, as an inhaled therapy for lung remodeling in pulmonary arterial hypertension
: A series of potent dual PDGFR/cKIT 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 it dosing. Compound 25 shows 24 hour occupancy of the PDGFR kinase domain, after a single it 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 vitro: in 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
Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension
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 <b>25</b> 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 vitro:in
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
Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension
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 <b>25</b> 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 vitro:in
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