69395-89-7Relevant articles and documents
Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors
Guo, Jing,Zhao, Fan,Yin, Wenbo,Zhu, Mingyue,Hao, Chenzhou,Pang, Yu,Wu, Tianxiao,Wang, Jian,Zhao, Dongmei,Li, Haitao,Cheng, Maosheng
, p. 197 - 209 (2018/06/12)
We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 μM, HCT116 IC50 = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.
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Bisphosphonates (BPs) are pyrophosphate analogues in which the oxygen in P-O-P has been replaced by a carbon, resulting in a metabolically stable P-C-P structure.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.
Studies on N-alkyl-2-(5-methyl-4-imidazolyl)ethylamines. Synthesis and effect on gastric secretion.
Vitali et al.
, p. 41,43 (2007/10/04)
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