144528-23-4Relevant articles and documents
Design and synthesis of pyrrolo[3,2- d ]pyrimidine human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors: Exploration of novel back-pocket binders
Kawakita, Youichi,Banno, Hiroshi,Ohashi, Tomohiro,Tamura, Toshiya,Yusa, Tadashi,Nakayama, Akiko,Miki, Hiroshi,Iwata, Hidehisa,Kamiguchi, Hidenori,Tanaka, Toshimasa,Habuka, Noriyuki,Sogabe, Satoshi,Ohta, Yoshikazu,Ishikawa, Tomoyasu
experimental part, p. 3975 - 3991 (2012/07/16)
To develop novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI50, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4-1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
Synthesis and preliminary biological evaluation of novel N-substituted 1-amino-3-[1-methyl(phenyl)-1H-indazol-4-yloxy]-propan-2-ols interesting as potential antiarrhythmic, local anaesthetic and analgesic agents
Mosti,Menozzi,Fossa,Filippelli,Gessi,Rinaldi,Falcone
, p. 963 - 972 (2007/10/03)
A series of indazoloxypropanolamines 7 and 8, pindolol isosteres, were synthezised to extend the structure activity relationship (SAR) which was observed in an earlier series of related derivatives. Compounds 7, characterized by methyl substitution on the N-1 indazole nucleus, generally exhibited significant antiarrhythmic, local anaesthetic and analgesic activities. The preliminary radioligand binding assay highlighted, in compounds 7, an interesting β1-affinity which can be well correlated to their antiarrhyhtmic activity. Analogues 8 characterized by a phenyl group on the N-1 indazole nucleus, were generally less active as antiarrhyhtmic agents but generally interesting as local anaesthetics. Due to the importance of the indazole moiety as a carrier of antiphlogistic activity, the two classes of derivatives 7 and 8 were evaluated for their NSAID behaviour. Once again, compounds 7 resulted having more interesting analgesic and antipyretic effects than analogues 8.
4-substituted 1-methyl-1H-indazoles with analgesic antiinflammatory and antipyretic activities
Mosti,Menozzi,Fossa,Schenone,Lampa,Parrillo,D'Amico,Rossi
, p. 567 - 584 (2007/10/02)
The synthesis of [(1-methyl-1H-indazol-4-yl)oxy]acetic acid 4, 1-methyl-1H-indazole-4-acetic acid 9, 2-(1-methyl-1H-indazol-4-yl)propanoic acid 15 and [[(1,5,6, 7-tetrahydro-1-methyl-4H-indazol-4-ylidene)amino]oxy]acetic acid 16, as well as of amides and esters derived from 4 and 9, starting from 1,5,6,7-tetrahydro-1-methyl-4H-indazol-4-one is described. Some of the above compounds showed weak antiinflammatory, analgesic, antipyretic and hypotensive activities in rats and mice, as well as moderate platelet antiaggregating effects in vitro.
