1. Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension
- Author
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Andrew C. Pearce, Sylvie Chamoin, Matthew Thomas, Loren Jon, Deborah Haggart, Sonia P. Roberts, Christopher Thomson, John Reilly, Vikki Furminger, Ian N. Bruce, Peter Drückes, Sarah Cross, Rowan Stringer, Ferheen Baig, Satish Dayal, Duncan Shaw, Irena Konstantinova, Alex Michael Saunders, Stephen Paul Collingwood, Ben Wen, Valentina Molteni, Christine Tomlins, Martin Hussey, Lilya Sviridenko, Pascal Furet, and Vince Yeh
- Subjects
Niacinamide ,0301 basic medicine ,Receptor, Platelet-Derived Growth Factor alpha ,Hypertension, Pulmonary ,Vascular Remodeling ,Pharmacology ,Muscle, Smooth, Vascular ,Permeability ,Cell Line ,Receptor, Platelet-Derived Growth Factor beta ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Administration, Inhalation ,Drug Discovery ,medicine ,Animals ,Receptors, Platelet-Derived Growth Factor ,Lung ,Cell Proliferation ,biology ,Cell growth ,Kinase ,Chemistry ,Membranes, Artificial ,medicine.disease ,Pulmonary hypertension ,In vitro ,Rats ,Molecular Docking Simulation ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Cell culture ,biology.protein ,Airway Remodeling ,Pyrazoles ,Molecular Medicine ,Platelet-derived growth factor receptor - 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 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.
- Published
- 2016
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