Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
CO2 and
H2 solubilities, CO2/H2 solubility
selectivities, CO2 diffusivities, and
solvent viscosities in 27 commercially available physical solvents
at 298 K were calculated from molecular simulations using the CHARMM36
all-atom force field for most solvents, and the simulation results
were compared with available experimental data. The van der Waals
radius parameters for solvents were slightly tuned to reproduce the
experimental solvent density. The simulated CO2 solubilities
are comparable with the experimental data, with an average absolute
difference of 28%. For the homologous compounds containing the −(OCH2CH2)– repeat unit, both simulated and experimental
data show that CO2 solubility decreases when the number
of repeat units is increased; CO2 solubilities in these
homologous compounds exhibit almost a perfect positive linear correlation
with the solvent free-volume fractions. The simulated H2 solubilities and CO2/H2 solubility selectivities
are also comparable with the experimental data, with differences of
22% and 17%, respectively. The H2 solubilities in all solvents
studied in this work correlate very well with the solvent free-volume
fractions, exhibiting a positive linear correlation coefficient of
0.84. Additionally, simulations show that CO2 solubility
decreases when the temperature is increased. In contrast, H2 solubility increases at elevated temperature, which is partly due
to the increased solvent free-volume fraction at elevated temperature.
Finally, although the viscosity difference tends to be large (30%–246%)
between simulation and experiment, both simulated and experimental
data exhibit a similar solvent viscosity trend. Furthermore, simulations
show that CO2 diffusivities in solvents are very strongly
correlated with the solvent viscosities and the relationship between
them is given by D
CO2
= (2.6
± 0.3) × 10–9/ηsolvent
0.59 ± 0.03.
This study presents the fabrication of a new mixed matrix membrane using two microporous polymers: a polymer of intrinsic microporosity PIM-1 and a benzimidazole linked polymer, BILP-101, and their CO separation properties from post-combustion flue gas. 17, 30 and 40 wt% loadings of BILP-101 into PIM-1 were tested, resulting in mechanically stable films showing very good interfacial interaction due to the inherent H-bonding capability of the constituent materials. Gas transport studies showed that BILP-101/PIM-1 membranes exhibit high CO permeability (7200 Barrer) and selectivity over N (15). The selected hybrid membrane was further tested for CO separation using actual flue gas from a coal-fired power plant.
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