- Discovery of G2019S-Selective Leucine Rich Repeat Protein Kinase 2 inhibitors with in vivo efficacy
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Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp = 0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.
- Fitch, William L.,Gajera, Chandresh R.,Lam, Grace,Le?niak, Robert K.,Montine, Thomas J.,Nguyen, Khanh C.,Nichols, R. Jeremy,Schonemann, Marcus,Smith, Mark,Zhao, Jing
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supporting information
(2022/01/08)
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- HETEROCYCLIC COMPOUNDS WITH AN ROR(GAMMA)T MODULATING ACTIVITY
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The present invention relates to a compound that may have an ROR(gamma)t modulating activity and can thus be useful in the treatment of cancer.
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Paragraph 0883
(2018/03/06)
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- HETEROTETRACYCLIC COMPOUNDS AS TPO MIMETICS
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The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated TPO activity, particularly diseases or disorders that involve thrombocytopenia.
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Page/Page column 32
(2009/04/24)
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- Cyclic amine derivatives and methods of use
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Selected compounds are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving pain, inflammation, and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page/Page column 37-38
(2010/02/14)
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- BICYCLIC COMPOUNDS HAVING BRADYKININ RECEPTORS AFFINITY AND PHARMACEUTICAL COMPOSITIONS THEREOF
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Selected compounds are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and
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- CYCLIC AMINE DERIVATIVES AND THEIR USE IN THE TREATMENT OF INFLAMMATION-RELATED DISORDERS MEDIATED BY BRADYKININ
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Compounds of formula (I) are effective for treatment of pain and diseases, such as inflammation mediated diseases. The invention encompasses novel compounds, pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving pain, inflammation mediated by Bradykinin. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes wherein q, t, R, Ra, Rb, Rc and R2 are as defined herein.
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Page 106; 107
(2010/02/09)
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