3 research outputs found
Interactions between β2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR
To
understand the relationship between structural properties of
the β2-adrenoceptor ligands and their interactions with membranes,
we have investigated the location and distribution of five β2
agonists with distinct clinical durations and onsets of action (indacaterol,
two indacaterol analogues, salmeterol and formoterol) in monounsaturated
model membranes using magic angle spinning NMR to measure these interactions
through both <sup>1</sup>H nuclear Overhauser enhancement (NOE) and
paramagnetic relaxation enhancement (PRE) techniques. The hydrophilic
aromatic groups of all five β2 agonists show maximum distribution
in the lipid/water interface, but distinct location and dynamic behavior
were observed for the lipophilic aromatic rings. Our study elucidates
at atomic level that the hydrophobicity and substitution geometry
of lipophilic groups play important roles in compound–lipid
interactions
Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension
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 <b>25</b> 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
Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension
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 <b>25</b> 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