Pulmonary arterial hypertension (PAH) is a devastating disease associated with high morbidity and mortality. The purpose of this proposal is to develop a novel highly selective platelet derived growth factor receptor (PDGFR) inhibitor for PAH that will be delivered by inhalation. Signaling through the PDGFR leads to smooth muscle cell proliferation which contributes to the development of PAH. The PDGFR inhibitor imatinib has shown efficacy in treating PAH in some patients. However, there are some concerns about off-target effects of imatinib because it also inhibits another kinase called Abl. The PDGFR inhibitors to be developed in this proposal are more selective than imatinib and do not inhibit Abl. This proposal will develop these novel inhibitors for direct pulmonary delivery. Because PAH involves the pulmonary arteriolar bed, direct delivery of the drug by inhalation will improve the therapeutic window: i.e., increase efficacy, and decrease systemic side effects. The approach will consist of the following steps: 1) Formulate the drug candidates for aerosolization and determine the respiratory deposition pattern of inhaled aerosol with SPECT gamma scintigraphy and three dimensional computed tomography. 2) Determine the inhaled and deposited mass of the drug candidates and pharmacokinetic distribution of the drug candidates. 3) Determine the efficacy and therapeutic window of lead drug candidates in a model of PAH. The effect of the drug candidates on pulmonary hypertension will be measured by continuous telemetry monitoring of pulmonary artery pressure. The effect of study drug on right ventricular function will be evaluated with echocardiography, and a new admittance technology to generate pressure-volume loops. Histology will be performed to evaluate the effect of the study drugs on the pulmonary pathology associated with PAH. The results of this project will lead to formulation of one of the lead candidates for use in humans and IND enabling studies. This new treatment could reduce the morbidity and mortality of PAH and thereby benefit patients and society.
Public Health Relevance: Pulmonary arterial hypertension is a devastating disease with a high morbidity and mortality. This project is relevant to public health because it will ultimately lead to a new treatment for pulmonary arterial hypertension.
Thesaurus Terms: "20-Norcrotalanan-11,15-Dione, 14,19-Dihydro-12,13-Dihydroxy-, (13alpha,14alpha)-; Address; Adverse Effects; Aerosols; Affect; Agonist; Alveolar; Animal Model; Animal Models And Related Studies; Area; Arterioles; Aspiration, Respiratory; Beds; Breathing; Cat Scan, X-Ray; Cat Scan; Ct X Ray; Ct Scan; Cardiac Output; Cardiopulmonary; Case Study; Cell Communication And Signaling; Cell Growth In Number; Cell Multiplication; Cell Proliferation; Cell Signaling; Cellular Proliferation; Chemicals; Chronic Myeloid Leukemia; Clinical Trials; Clinical Trials, Unspecified; Common Rat Strains; Computed Tomography; Computerized Axial Tomography (Computerized Tomography); Computerized Tomography, X-Ray; Deposit; Deposition; Development; Disease; Disorder; Dose; Drug Formulations; Drug Kinetics; Drugs; Ec 2.7; Emi Scan; Echocardiogram; Echocardiography; Formulation; Formulations, Drug; Gamma Camera Imaging; Goals; Histology; Human; Human, General; Imatinib; Inhalation; Inhaling; Inspiration, Respiratory; Intracellular Communication And Signaling; Kinases; Lead; Leiomyocyte; Lesion; Leukemia, Granulocytic, Chronic; Lung; Lung Parenchyma; Lung Tissue; Mammals, Rats; Man (Taxonomy); Man, Modern; Measures; Medical Imaging, Single Photon Emission Computed Tomography; Medication; Modeling; Monitor; Monocrotaline; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; Myelocytic Leukemia, Chronic; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Chronic; Myocytes, Smooth Muscle; Pdgfr; Ptk Inhibitors; Ptk Receptors; Particle Size; Pathogenesis; Pathology; Pathway Interactions; Patients; Pattern; Pb Element; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Phosphotransferases; Platelet-Derived Growth Factor Receptor; Play; Pneumonectomy; Pressure; Pressure- Physical Agent; Protein Tyrosine Kinase Inhibitors; Public Health; Pulmonary Artery; Pulmonary Hypertension; Pulmonary Pathology; Pulmonary Artery Structure; Rtk; Radionuclide Imaging; Radionuclide Tomography, Single-Photon Emission-Computed; Rat; Rattus; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Receptors, Pdgf; Refractory; Respiratory System, Lung; Right Ventricular Function; Role; Sbir; Sbirs (R43/44); Spect; Spect Imaging; Scanning, Radioisotope; Scintigraphy; Signal Transduction; Signal Transduction Systems; Signaling; Small Business Innovation Research; Small Business Innovation Research Grant; Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; Societies; Staging; Structure Of Arteriole; Structure Of Parenchyma Of Lung; Tk Inhibitors; Technology; Telemetries; Telemetry; Therapeutic; Time; Tomodensitometry; Tomography, Emission-Computed, Single-Photon; Tomography, Xray Computed; Toxic Effect; Toxicities; Transmembrane Receptor Protein Tyrosine Kinase; Transphosphorylases; Transthoracic Echocardiography; Treatment Efficacy; Treatment Side Effects; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Inhibitor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; United States; X-Ray Computed Tomography; Arteriole; Biological Signal Transduction; Case Report; Catscan; Clinical Investigation; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; Disease/Disorder; Drug Candidate; Drug Inhalation; Drug/Agent; Heart Output; Heart Sonography; Heavy Metal Pb; Heavy Metal Lead; Hemodynamics; Improved; Inhibitor; Inhibitor/Antagonist; Innovate; Innovation; Innovative; Inspiration; Meetings; Model Organism; Novel; Pathway; Patient Population; Pressure; Public Health Medicine (Field); Public Health Relevance; Pulmonary; Pulmonary Arterial Hypertension; Radionuclide Imaging/Scanning; Radionuclide Scanning; Respiratory; Side Effect; Social Role; Sound Measurement; Therapeutic Efficacy; Therapeutically Effective; Therapy Adverse Effect; Treatment Adverse Effect"
