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

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

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.

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