Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension

Duncan E Shaw; Ferheen Baig; Ian Bruce; Sylvie Chamoin; Stephen P Collingwood; Sarah Cross; Satish Dayal; Peter Drückes; Pascal Furet; Vikki Furminger; Deborah Haggart; Martin Hussey; Irena Konstantinova; Jon C Loren; Valentina Molteni; Sonia Roberts; John Reilly; Alex M Saunders; Rowan Stringer; Lilya Sviridenko; Matthew Thomas; Christopher G Thomson; Christine Tomlins; Ben Wen; Vince Yeh; Andrew C Pearce

doi:10.1021/acs.jmedchem.6b00703

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. 2016 Sep 8;59(17):7901-14. doi: 10.1021/acs.jmedchem.6b00703. Epub 2016 Aug 19.

Authors

Affiliations

¹ Novartis Institutes of Biomedical Research (NIBR) , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
² NIBR , Basel Fabrikstrasse 2, 4056 Basel, Switzerland.
³ Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.

PMID: 27502700
DOI: 10.1021/acs.jmedchem.6b00703

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.

MeSH terms

Administration, Inhalation
Airway Remodeling / drug effects*
Animals
Cell Line
Cell Proliferation
Hypertension, Pulmonary / drug therapy*
Hypertension, Pulmonary / pathology
Lung / blood supply
Membranes, Artificial
Molecular Docking Simulation
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / pathology
Niacinamide / analogs & derivatives*
Niacinamide / chemical synthesis
Niacinamide / chemistry
Niacinamide / pharmacology
Permeability
Proto-Oncogene Proteins c-kit / antagonists & inhibitors
Proto-Oncogene Proteins c-kit / chemistry
Pyrazoles / chemical synthesis
Pyrazoles / chemistry*
Pyrazoles / pharmacology
Rats
Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor alpha / chemistry
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta / chemistry
Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
Receptors, Platelet-Derived Growth Factor / chemistry
Structure-Activity Relationship
Vascular Remodeling / drug effects*

Substances

Membranes, Artificial
N-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo(1,5-a)pyridine-3-carboxamide
Pyrazoles
Niacinamide
Proto-Oncogene Proteins c-kit
Receptor, Platelet-Derived Growth Factor alpha
Receptor, Platelet-Derived Growth Factor beta
Receptors, Platelet-Derived Growth Factor