- SUBSTITUTED AMINO TRIAZOLES USEFUL AS CHITINASE INHIBITORS
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Disclosed are amino triazole compounds of formula (I). These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
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Paragraph 0275; 0290; 0291
(2021/02/05)
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- Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis
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Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.
- Koralewski, Robert,Dymek, Barbara,Mazur, Marzena,Sklepkiewicz, Piotr,Olejniczak, Sylwia,Czestkowski, Wojciech,Matyszewski, Krzysztof,Andryianau, Gleb,Niedziejko, Piotr,Kowalski, Michal,Gruza, Mariusz,Borek, Bart?omiej,Jedrzejczak, Karol,Bartoszewicz, Agnieszka,Pluta, El?bieta,Rymaszewska, Aleksandra,Kania, Magdalena,Rejczak, Tomasz,Piasecka, Sylwia,Mlacki, Michal,Mazurkiewicz, Marcin,Piotrowicz, Micha?,Salamon, Magdalena,Zagozdzon, Agnieszka,Napiorkowska-Gromadzka, Agnieszka,Bartlomiejczak, Aneta,Mozga, Witold,Dobrzański, Pawe?,Dzwonek, Karolina,Golab, Jakub,Nowotny, Marcin,Olczak, Jacek,Golebiowski, Adam
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p. 15527 - 15540
(2020/11/17)
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- SUBSTITUTED AMINO TRIAZOLES USEFUL AS HUMAN CHITINASE INHIBITORS
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Disclosed are amino triazole compounds substituted with a piperidinyl ring that is itself substituted with a heterocyclic ring. These compounds are inhibitors of acidic mammalian chitinase and chitotriosidase. Also disclosed are methods of using the compounds to treat asthma reactions caused by allergens, as well as acute and chronic inflammatory diseases, autoimmune diseases, dental diseases, neurologic diseases, metabolic diseases, liver diseases, polycystic ovary syndrome, endometriosis, and cancer.
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Page/Page column 81; 93; 94
(2017/03/21)
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- Electronic effects of aryl-substituted bis(oxazoline) ligands on the outcome of asymmetric copper-catalysed C-H insertion and aromatic addition reactions
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The effect of the modification of bis(oxazoline) ligands on the outcome of copper-catalysed C-H insertion and aromatic addition reactions is described. In general, these reactions display minimum sensitivity in terms of enantiocontrol to variation of the electronic properties of the aryl moiety of the ligand however, some influence is observed for C-H insertions employing naphthyl-substituted bis(oxazolines) and for aromatic addition reactions of biphenyl diazo ketone substrates. The synthesis of the modified bis(oxazolines), which include four novel structures, is also described.
- Slattery, Catherine N.,O'Keeffe, Sarah,Maguire, Anita R.
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p. 1265 - 1275
(2013/11/19)
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- New thiazole carboxamides as potent inhibitors of Akt kinases
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A new series of 2-substituted thiazole carboxamides were identified as potent pan inhibitors against all three isoforms of Akt (Akt1, Akt2 and Akt3) by systematic optimization of weak screening hit N-(1-amino-3-phenylpropan-2-yl)- 2-phenylthiazole-5-carboxamide (1). One of the most potent compounds, 5m, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC50 values of 25, 196 and 24 nM, respectively. The compound also potently inhibited the phosphorylation of downstream MDM2 and GSK3β proteins, and displayed strongly antiproliferative activity in prostate cancer cells. The inhibitors might serve as lead compounds for further development of novel effective anticancer agents.
- Chang, Shaohua,Zhang, Zhang,Zhuang, Xiaoxi,Luo, Jinfeng,Cao, Xianwen,Li, Honglin,Tu, Zhengchao,Lu, Xiaoyun,Ren, Xiaomei,Ding, Ke
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supporting information; experimental part
p. 1208 - 1212
(2012/03/11)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 58
(2010/12/31)
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- Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
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This invention relates to 2-arylimino heterocycles, including 2-arylimino-1,3-thiazolidines, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazines, 2-arylimino-1,3-thiazolidin-4-ones, 2-arylimino-1,3-thiazolidin-5-ones, and 2-arylimino-1,3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.
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Page column 117
(2010/02/05)
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