486460-26-8Relevant articles and documents
1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors
Dolbois, Aymeric,Bedi, Rajiv K.,Bochenkova, Elena,Müller, Anna,Moroz-Omori, Elena V.,Huang, Danzhi,Caflisch, Amedeo
, p. 12738 - 12760 (2021/09/13)
N6-methyladenosine (m6A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m6A regulation machinery, is a key player in a variety of diseases including several types of cancer, type 2 diabetes, and viral infections. Here we report on a protein crystallography-based medicinal chemistry optimization of a METTL3 hit compound that has resulted in a 1400-fold potency improvement (IC50 of 5 nM for the lead compound 22 (UZH2) in a time-resolved F?rster resonance energy transfer (TR-FRET) assay). The series has favorable ADME properties as physicochemical characteristics were taken into account during hit optimization. UZH2 shows target engagement in cells and is able to reduce the m6A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.
Process Development Overcomes a Challenging Pd-Catalyzed C-N Coupling for the Synthesis of RORc Inhibitor GDC-0022
Sirois, Lauren E.,Lao, David,Xu, Jie,Angelaud, Rémy,Tso, Jerry,Scott, Brandon,Chakravarty, Paroma,Malhotra, Sushant,Gosselin, Francis
, p. 567 - 578 (2020/04/15)
Process development for a multi-kilogram-scale synthesis of GDC-0022, an inhibitor of retinoic acid receptor-related orphan receptor γ(RORc), is described. Delivery of the active pharmaceutical ingredient (API) relied on diastereoselective preparation of a six-membered sultam building block, as well as execution of its benzylation under heterogeneous conditions. Investigation and optimization of a challenging late-stage palladium-catalyzed C-N coupling of a bicyclic amine were likewise central to synthetic efforts. Understanding of this key reaction, as well as the development of API salt forms and isolations, ultimately enabled a successful reaction at 8.0 kg scale, utilizing 1.0 mol % XantPhos-Pd-G2 as precatalyst and, in turn, preparation of >5.0 kg of GDC-0022 tosylate salt for preclinical needs.
ALDH2 ACTIVATOR
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Paragraph 0109-0110, (2019/08/22)
The present invention provides a compound represented by formula (1): or pharmaceutically acceptable salt thereof, wherein X and Y are the same or different from each other and represent a hydrogen atom, a halogen atom, a C1-6 alkyl group, or a C1-6 alkoxy group, wherein the C1-6 alkoxy group may be substituted with a C1-6 alkoxy group, andZ and W are the same or different from each other and represent a hydrogen atom, a halogen atom, or a C1-6 alkyl group.
NOVEL ANTIBIOTICS AND METHODS OF USING SAME
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Page/Page column 60, (2018/05/16)
The present invention includes novel 3,6-diazabicyclo[3.1.1]heptane antibiotic compounds and any salts or solvates thereof. The present invention further includes methods of preparing such compounds, and methods of treating bacterial infection in a subjec
BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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Paragraph 0181, (2015/12/30)
The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.
LYSOPHOSPHATIDIC ACID RECEPTOR ANTAGONISTS
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Paragraph 1321; 1323, (2014/07/23)
Compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat, prevent or diagnose diseases, disorders, or conditions associated with one or more of the lysophosphatidic acid receptors are provided.