- Selective Inhibitors of G2019S-LRRK2 Kinase Activity
-
Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.
- Garofalo, Albert W.,Bright, Jessica,De Lombaert, Stéphane,Toda, Alyssa M. A.,Zobel, Kerry,Andreotti, Daniele,Beato, Claudia,Bernardi, Silvia,Budassi, Federica,Caberlotto, Laura,Gao, Peng,Griffante, Cristiana,Liu, Xinying,Mengatto, Luisa,Migliore, Marco,Sabbatini, Fabio Maria,Sava, Anna,Serra, Elena,Vincetti, Paolo,Zhang, Mingliang,Carlisle, Holly J.
-
p. 14821 - 14839
(2020/11/30)
-
- FUSED TETRAZOLES AS LRRK2 INHIBITORS
-
The present invention is directed to fused tetrazoles of formula (IA) which are inhibitors of LRRK2 and are useful in the treatment of CNS disorders.
- -
-
Page/Page column 152-153
(2019/12/04)
-
- Thiophene compound Tetrahydrobenza and (by machine translation)
-
The purpose of this invention is to provide with intestinal phosphate transport protein inhibit function (NPT-IIb), hyperphosphatemia as a therapeutic and/or preventive agent for Tetrahydrobenza the effective ingredient of benzothiophene compound or its stereoisomers, geometric isomers, tautomers, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug and pharmaceutical composition. (by machine translation)
- -
-
Paragraph 0383; 0384
(2016/10/09)
-
- Enantioselective α-benzylation of aldehydes via photoredox organocatalysis
-
The first enantioselective aldehyde α-benzylation using electron-deficient aryl and heteroaryl substrates has been accomplished. The productive merger of a chiral imidazolidinone organocatalyst and a commercially available iridium photoredox catalyst in the presence of household fluorescent light directly affords the desired homobenzylic stereogenicity in good to excellent yield and enantioselectivity. The utility of this methodology has been demonstrated via rapid access to an enantioenriched drug target for angiogenesis suppression.
- Shih, Hui-Wen,Vander Wal, Mark N.,Grange, Rebecca L.,MacMillan, David W. C.
-
supporting information; experimental part
p. 13600 - 13603
(2010/11/18)
-