848133-04-0Relevant articles and documents
AGENTS FOR USE IN THE TREATMENT OF AMYLOIDOSIS
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, (2022/04/03)
The present invention relates to compounds for stabilising the native tetrameric form of transthyretin and protecting it from proteolytic cleavage; compounds for use in the prevention and treatment of transthyretin amyloidosis; and agents and medicaments comprising such compounds. The compounds are based on a general structure A-L-B, wherein A is a group of formula (II) or of formula (III): or of formula (IV) or of formula (V) B is a group of formula (III), (IV), or (V), or a group of formula (VI) or a group of formula –R10Z, wherein: Z is selected from -CO2R', -CONR'R'', -SO2R' wherein R' and R'' are independently H or C1-C4 alkyl; and R10 is a C1-C4 alkylene or alkenylene group; and L represents a linker group which is a saturated or unsaturated chain of 5 to 13 carbon atoms.
Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity
Tsou, Hwei-Ru,Overbeek-Klumpers, Elsebe G.,Hallett, William A.,Reich, Marvin F.,Floyd, M. Brawner,Johnson, Bernard D.,Michalak, Ronald S.,Nilakantan, Ramaswamy,Discafani, Carolyn,Golas, Jonathan,Rabindran, Sridhar K.,Shen, Ru,Shi, Xiaoqing,Wang, Yu-Fen,Upeslacis, Janis,Wissner, Allan
, p. 1107 - 1131 (2007/10/03)
A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino) quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)-quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.
Kinetic stabilization of an oligomeric protein by a single ligand binding event
Wiseman, R. Luke,Johnson, Steven M.,Kelker, Matthew S.,Foss, Ted,Wilson, Ian A.,Kelly, Jeffery W.
, p. 5540 - 5551 (2007/10/03)
Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (I) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of TTR·I in solution to the exclusion of TTR·I2 and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., Kd1 in nanomolar range and Kd2 in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.
