title: Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension.
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.
authors: Novartis Institutes of Biomedical Research (NIBR) , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors: Duncan E
authors: DE
authors: Shaw
authors: Ferheen
authors: F
authors: Baig
authors: Ian
authors: I
authors: Bruce
authors: NIBR , Basel Fabrikstrasse 2, 4056 Basel, Switzerland.
authors: Sylvie
authors: S
authors: Chamoin
authors: Stephen P
authors: SP
authors: Collingwood
authors: Novartis Institutes of Biomedical Research (NIBR) , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors: Sarah
authors: S
authors: Cross
authors: Satish
authors: S
authors: Dayal
authors: NIBR , Basel Fabrikstrasse 2, 4056 Basel, Switzerland.
authors: Peter
authors: P
authors: Drückes
authors: NIBR , Basel Fabrikstrasse 2, 4056 Basel, Switzerland.
authors: Pascal
authors: P
authors: Furet
authors: Vikki
authors: V
authors: Furminger
authors: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors: Deborah
authors: D
authors: Haggart
authors: Martin
authors: M
authors: Hussey
authors: Irena
authors: I
authors: Konstantinova
authors: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors: Jon C
authors: JC
authors: Loren
authors: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors: Valentina
authors: V
authors: Molteni
authors: Sonia
authors: S
authors: Roberts
authors: John
authors: J
authors: Reilly
authors: Alex M
authors: AM
authors: Saunders
authors: Rowan
authors: R
authors: Stringer
authors: Lilya
authors: L
authors: Sviridenko
authors: Matthew
authors: M
authors: Thomas
authors: Novartis Institutes of Biomedical Research (NIBR) , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
authors: Christopher G
authors: CG
authors: Thomson
authors: Christine
authors: C
authors: Tomlins
authors: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors: Ben
authors: B
authors: Wen
authors: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors: Vince
authors: V
authors: Yeh
authors: Andrew C
authors: AC
authors: Pearce
mesh_terms: D000280:Administration, Inhalation; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology; D008168:Lung / Q000098:blood supply; D008567:Membranes, Artificial; D062105:Molecular Docking Simulation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000737:chemistry; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000737:chemistry; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000737:chemistry; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D008567:Membranes, Artificial; C000621123: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; D011720:Pyrazoles; D009536:Niacinamide; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor