- 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors
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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.
- Dolbois, Aymeric,Bedi, Rajiv K.,Bochenkova, Elena,Müller, Anna,Moroz-Omori, Elena V.,Huang, Danzhi,Caflisch, Amedeo
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p. 12738 - 12760
(2021/09/13)
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- FAAH INHIBITORS
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The present disclosure relates to compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the com
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- 5-lipoxygenase-activating protein (FLAP) inhibitors. Part 4: Development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin- 2-ylmethoxy)-1 H -indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor
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The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2- ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB4 inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC50 of 76 nM for inhibition of LTB4 in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.
- Stock, Nicholas S.,Bain, Gretchen,Zunic, Jasmine,Li, Yiwei,Ziff, Jeannie,Roppe, Jeffrey,Santini, Angelina,Darlington, Janice,Prodanovich, Pat,King, Christopher D.,Baccei, Christopher,Lee, Catherine,Rong, Haojing,Chapman, Charles,Broadhead, Alex,Lorrain, Dan,Correa, Lucia,Hutchinson, John H.,Evans, Jilly F.,Prasit, Peppi
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p. 8013 - 8029
(2012/03/08)
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- Triazolopyridine cannabinoid receptor 1 antagonists
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The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents, and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formula: including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein R1, R2, R3, R4 and R5 are described herein.
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- Heterocycles substituted pyridine derivatives and antifungal agent containing thereof
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An object of the present invention is to provide an antifungal agent which has excellent antifungal effects and is superior in terms of its physical properties, safety and metabolic stability. According to the present invention, there is disclosed a compound represented by the following formula (I), or a salt thereof: wherein R1 represents a hydrogen atom, a halogen atom, an amino group, a C1-6 alkyl group, a C1-6 alkoxy group or a C1-6 alkoxy C1-6 alkyl group; R2 represents a hydrogen atom, a C1-6 alkyl group, an amino group or a di C1-6 alkylamino group; one of X and Y is a nitrogen atom while the other is a nitrogen atom or an oxygen atom; ring A represents a 5- or 6-member heteroaryl ring or a benzene ring which may have a halogen atom, or 1 or 2 C1-6 alkyl groups; Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, —CH2O—, —OCH2—, —NH—, —CH2NH—, —NHCH2—, —CH2S—, or —SCH2—; R3 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5- or 6-member heteroaryl group, or 5- or 6-member non-aromatic heterocyclic group which may have 1 or 2 substituents; and R4 represents a hydrogen atom or a halogen atom.
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Page/Page column 115
(2010/11/27)
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- Triazolopyrimidine cannabinoid receptor 1 antagonists
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The present application describes compounds according to both Formulas I and II, pharmaceutical compositions comprising at least one compound according to either Formula I or II and optionally one or more additional therapeutic agents, and methods of treatment using the compounds according to Formulas I and II both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formulas: including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein R1, R2, R3, R4 and R5 are described herein.
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Page/Page column 48
(2010/11/25)
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- 2--1H-thienoimidazoles. A Novel Class of Gastric H+/K+-ATPase Inhibitors
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2-thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K+-ATPase.The isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo.Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thienoimidazole lead to highly active compounds with a favorable chemical stability.Various substitution patterns in the thienoimidazole moiety result in lower biological activity.The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation.Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H+/K+-ATPase blocker introduced on the market.
- Weidmann, Klaus,Herling, Andreas W.,Lang, Hans-Jochen,Scheunemann, Karl-Heinz,Rippel, Robert,et al.
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p. 438 - 450
(2007/10/02)
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