1101173-77-6Relevant articles and documents
Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor
Waaler, Jo,Leenders, Ruben G. G.,Sowa, Sven T.,Alam Brinch, Shoshy,Lycke, Max,Nieczypor, Piotr,Aertssen, Sjoerd,Murthy, Sudarshan,Galera-Prat, Albert,Damen, Eddy,Wegert, Anita,Nazaré, Marc,Lehti?, Lari,Krauss, Stefan
supporting information, p. 6834 - 6846 (2020/08/14)
Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
1,2,4-TRIAZOLE DERIVATIVES AS TANKYRASE INHIBITORS
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Page/Page column 52, (2020/01/11)
The present invention relates to compounds of formula (I), tautomers, stereoisomers, pharmaceutically acceptable salts and pro-drugs thereof, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in therapy wherein a dashed line indicates an optional bond; X represents: a 5- or 6-membered, unsaturated heterocyclic group optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from halogen (i.e. F, C1, Br, I), C1-6 alkyl (e.g. C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), C1-6 alkoxy (e.g. C1-3 alkoxy), -CN, -NO2, -N(R)2, and -SO2R (where each R is independently H or C1-6 alkyl, e.g. H or C1-3 alkyl); a C3-5 cycloalkyl group optionally substituted by one or more (e.g. 1 or 2) substituents independently selected from C1-6 alkyl (preferably C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), and C1-6 alkoxy (e.g. C1-3 alkoxy); or an aryl group optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from halogen (i.e. F, C1, Br, I), C1-6 alkyl (e.g C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), and C1-6 alkoxy (e.g. C1-3 alkoxy); Y represents: an aryl or heteroaryl group optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from halogen (i.e. F, Cl, Br, I), C1-6 alkyl (e.g C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), and C1-6 alkoxy (e.g. C1-3 alkoxy); a 5- or 6-membered, saturated heterocyclic group optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from C1-6 alkyl (preferably C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), and C1-6 alkoxy (e.g. C1-3 alkoxy); or a C3-6 cycloalkyl group optionally substituted by one or more (e.g. 1 or 2) substituents independently selected from C1-6 alkyl (preferably C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), and C1-6 alkoxy (e.g. C1-3 alkoxy); and Z represents: an aryl group optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from halogen (i.e. F, Cl, Br, I), C1-6 alkyl (e.g. C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), C1-6 alkoxy (e.g. C1-3 alkoxy), -CN, -NO2, -N(R)2, and -SO2R (where each R is independently H or C1-6 alkyl, e.g. H or C1-3 alkyl); or an unsaturated, 5- to 10-membered mono- or bicyclic heterocyclic group optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from halogen (i.e. F, C1, Br, I), C1-6 alkyl (e.g. C1-3 alkyl), C1-6 haloalkyl (e.g. C1-3 haloalkyl), C1-6 alkoxy (e.g. C1-3 alkoxy), -CN, -NO2, -N(R)2, and -SO2R (where each R is independently H or C1-6 alkyl, e.g. H or C1-3 alkyl). These compounds find particular use in the treatment and/or prevention of a disease or disorder responsive to inhibition of tankyrase 1 and/or 2, for example a disorder which is mediated by tankyrase 1 and/or 2 such as cancer.
Indoleamine-2,3-dioxygenase inhibitor as well as preparation method and application thereof
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, (2019/08/12)
The invention provides a compound as shown in a formula (I). The invention also relates to a pharmaceutical composition containing the compound of the formula (I) and application of the compound to preparation of an indoleamine-2,3-dioxygenase (IDO) inhibitor drug. The compound prepared by the method of the invention has an obvious inhibiting effect on IDO protease and is stable in metabolism in vivo. The compound or a pharmaceutical composition thereof provided by the invention can be used for preparing the IDO inhibitor drug, and can also be used for preparing medicines for preventing and/ortreating diseases with pathological characteristics of an IDO-mediated tryptophan metabolic pathway.
