ABSTRACT
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.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indazoles/chemistry , Indazoles/pharmacology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Animals , Brain/metabolism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Humans , Indazoles/administration & dosage , Indazoles/pharmacokinetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Male , Molecular Docking Simulation , Parkinson Disease/drug therapy , Parkinson Disease/enzymology , Rats , Rats, WistarABSTRACT
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 CO2 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 CO2 permeability (7200 Barrer) and selectivity over N2 (15). The selected hybrid membrane was further tested for CO2 separation using actual flue gas from a coal-fired power plant.
ABSTRACT
We have developed second-generation monomers 1 and 2 and improved conditions for rapidly and simultaneously closing multiple diketopiperazines on solid support. These new conditions involve either the microwave heating of a suspension of solid-supported amino-tetrafluoropropyl esters in acetic acid/triethylamine catalyst solution or continuous flow of catalyst solution through the resin, heated in a flow cell apparatus. We demonstrate that the new monomers 1 and 2 can be combined with the new conditions easily to synthesize previously inaccessible hetero and homo spiro ladder oligomers 3 and 4 and others.
