129488-00-2Relevant articles and documents
Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
Prasad, Bagineni,Jamroskovic, Jan,Bhowmik, Sudipta,Kumar, Rajendra,Romell, Tajanena,Sabouri, Nasim,Chorell, Erik
, p. 7926 - 7938 (2018/06/15)
Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.
LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS FACTOR XA INHIBITORS
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Paragraph 0741, (2017/04/28)
The present application describes lactam-containing compounds and derivatives thereof of Formula I: P4—P-M-M4??I or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.
Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors
Varnes, Jeffrey G.,Wacker, Dean A.,Jacobson, Irina C.,Quan, Mimi L.,Ellis, Christopher D.,Rossi, Karen A.,He, Ming Y.,Luettgen, Joseph M.,Knabb, Robert M.,Bai, Steven,He, Kan,Lam, Patrick Y.S.,Wexler, Ruth R.
, p. 6481 - 6488 (2008/03/18)
A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding Kis, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.
