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

被引：18

作者：

Shaw, Duncan E. ^{[1
]}

Baig, Ferheen ^{[2
]}

Bruce, Ian ^{[3
]}

Chamoin, Sylvie ^{[5
]}

Collingwood, Stephen P. ^{[3
]}

Cross, Sarah ^{[1
]}

Dayal, Satish ^{[2
]}

Drueckes, Peter ^{[5
]}

Furet, Pascal ^{[5
]}

Furminger, Vikki ^{[3
]}

Haggart, Deborah ^{[6
]}

Hussey, Martin ^{[4
]}

Konstantinova, Irena ^{[4
]}

Loren, Jon C. ^{[6
]}

Molteni, Valentina ^{[6
]}

Roberts, Sonia ^{[4
]}

Reily, John ^{[3
]}

Saunders, Alex M. ^{[3
]}

Stringer, Rowan ^{[2
]}

Sviridenko, Lilya ^{[3
]}

Thomas, Matthew ^{[4
]}

Thomson, Christopher G. ^{[1
]}

Tomlin, Christine ^{[4
]}

Wen, Ben ^{[6
]}

Yeh, Vince ^{[6
]}

Pearce, Andrew C. ^{[4
]}

机构：

[1] NIBR, 100 Technol Sq, Cambridge, MA 02139 USA

[2] NIBR Horsham, Metab & Pharmacokinet, Wimblehurst Rd, Horsham RH12 5AB, W Sussex, England

[3] NIBR Horsham, Global Discovery Chem, Wimblehurst Rd, Horsham RH12 5AB, W Sussex, England

[4] NIBR Horsham, Resp Dis, Wimblehurst Rd, Horsham RH12 5AB, W Sussex, England

[5] NIBR, Basel Fabrikstr 2, CH-4056 Basel, Switzerland

[6] Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 17期

关键词：

IMMOBILIZED ARTIFICIAL MEMBRANE; ALBUMIN-BINDING; DISCOVERY; DIAGNOSIS; KINASE; MODEL;

D O I：

10.1021/acs.jmedchem.6b00703

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7901 / 7914

页数：14

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