52353-66-9Relevant academic research and scientific papers
Discovery and Optimization of 2 H-1λ2-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer
Rohde, Jason M.,Karavadhi, Surendra,Pragani, Rajan,Liu, Li,Fang, Yuhong,Zhang, Weihe,McIver, Andrew,Zheng, Hongchao,Liu, Qingyang,Davis, Mindy I.,Urban, Daniel J.,Lee, Tobie D.,Cheff, Dorian M.,Hollingshead, Melinda,Henderson, Mark J.,Martinez, Natalia J.,Brimacombe, Kyle R.,Yasgar, Adam,Zhao, Wei,Klumpp-Thomas, Carleen,Michael, Sam,Covey, Joseph,Moore, William J.,Stott, Gordon M.,Li, Zhuyin,Simeonov, Anton,Jadhav, Ajit,Frye, Stephen,Hall, Matthew D.,Shen, Min,Wang, Xiaodong,Patnaik, Samarjit,Boxer, Matthew B.
, p. 4913 - 4946 (2021/05/07)
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
MUTANT IDH1 INHIBITORS USEFUL FOR TREATING CANCER
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Paragraph 0173, (2016/07/27)
Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed The variables A, B, Y, Z, X1, X2, R1-4 and R13-18 are disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing compounds of Formula I or Formula II and methods of treatment comprising administering compounds of Formula I and Formula II are also disclosed.
5-Substituted imidazole-4-acetic acid analogues: Synthesis, modeling, and pharmacological characterization of a series of novel γ-aminobutyric acidC receptor agonists
Madsen, Christian,Jensen, Anders A.,Liljefors, Tommy,Kristiansen, Uffe,Nielsen, Birgitte,Hansen, Camilla P.,Larsen, Mogens,Ebert, Bjarke,Bang-Andersen, Benny,Krogsgaard-Larsen, Povl,Fr?lund, Bente
, p. 4147 - 4161 (2008/02/13)
A series of ring-substituted analogues of imidazole-4-acetic acid (IAA, 4), a partial agonist at both GABAA and GABAC receptors (GABA = γ-aminobutyric acid), have been synthesized. The synthesized compounds 8a-1 have been evaluated a
Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa)
Widler, Leo,Jaeggi, Knut A.,Glatt, Markus,Müller, Klaus,Bachmann, Rolf,Bisping, Michael,Born, Anne-Ruth,Cortesi, Reto,Guiglia, Gabriela,Jeker, Heidi,Klein, Rémy,Ramseier, Ueli,Schmid, Johann,Schreiber, Gerard,Seltenmeyer, Yves,Green, Jonathan R.
, p. 3721 - 3738 (2007/10/03)
Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure. Pamidronate (1b, Novartis), a second-generation BP, was the starting point for extensive SAR studies. Small changes of the structure of pamidronate lead to marked improvements of the inhibition of osteoclastic resorption potency. Alendronate (1c, MSD), with an extra methylene group in the N-alkyl chain, and olpadronate (1h, Gador), the N,N-dimethyl analogue, are about 10 times more potent than pamidronate. Extending one of the N-methyl groups of olpadronate to a pentyl substituent leads to ibandronate (1k, Roche, Boehringer-Mannheim), which is the most potent close analogue of pamidronate. Even slightly better antiresorptive potency is achieved with derivatives having a phenyl group linked via a short aliphatic tether of three to four atoms to nitrogen, the second substituent being preferentially a methyl group (e.g., 4g, 4j, 5d, or 5r). The most potent BPs are found in the series containing a heteroaromatic moiety (with at least one nitrogen atom), which is linked via a single methylene group to the geminal bisphosphonate unit. Zoledronic acid (6i), the most potent derivative, has an ED50 of 0.07 mg/kg in the TPTX in vivo assay after sc administration. It not only shows by far the highest therapeutic ratio when comparing resorption inhibition with undesired inhibition of bone mineralization but also exhibits superior renal tolerability. Zoledronic acid (6i) has thus been selected for clinical development under the registered trade name Zometa. The results of the clinical trials indicate that low doses are both efficacious and safe for the treatment of tumor-induced hypercalcemia, Paget's disease of bone, osteolytic metastases, and postmenopausal osteoporosis.
