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.
Duncan E Shaw  1 ,  Ferheen Baig ,  Ian Bruce ,  Sylvie Chamoin  2 ,  Stephen P Collingwood ,  Sarah Cross  1 ,  Satish Dayal ,  Peter Drückes  2 ,  Pascal Furet  2 ,  Vikki Furminger ,  Deborah Haggart  3 ,  Martin Hussey ,  Irena Konstantinova ,  Jon C Loren  3 ,  Valentina Molteni  3 ,  Sonia Roberts ,  John Reilly ,  Alex M Saunders ,  Rowan Stringer ,  Lilya Sviridenko ,  Matthew Thomas ,  Christopher G Thomson  1 ,  Christine Tomlins ,  Ben Wen  3 ,  Vince Yeh  3 ,  Andrew C Pearce
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.