Shaw, Duncan, Baig, Ferheen, Bruce, Ian, Chamoin, Sylvie, Collingwood, Stephen, Cross, Sarah, Dayal, Satish, Drueckes, Peter, Furet, Pascal, Furminger, Vikki, Haggart, Deborah, Hussey, Martin, Konstantinova, Irena, Loren, Jon, Molteni, Valentina, Roberts, Sonia, Reilly, John, Saunders, Alex, Stringer, Rowan, Sviridenko, Lilya, Thomas, Matthew, Thomson, Christopher, Tomlins, Christine, Wen, Ben, Yeh, Vince and Pearce, Andrew (2016) Optimization of PDGFR inhibitors for duration of action, as an inhaled therapy for lung remodeling in pulmonary arterial hypertension. Journal of Medicinal chemistry, 59 (17). pp. 7901-7914. ISSN DOI: 10.1021/acs.jmedchem.6b00703

Abstract

: A series of potent dual PDGFR/cKIT 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 it dosing. Compound 25 shows 24 hour occupancy of the PDGFR kinase domain, after a single it 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.

Item Type:	Article
Date Deposited:	09 Nov 2016 00:45
Last Modified:	09 Nov 2016 00:45
URI:	https://oak.novartis.com/id/eprint/29092