206990-64-9Relevant articles and documents
A chemical chaperone-based drug candidate is effective in a mouse model of amyotrophic lateral sclerosis (ALS)
Getter, Tamar,Zaks, Ilana,Barhum, Yael,Ben-Zur, Tali,B?selt, Sebastian,Gregoire, Simpson,Viskind, Olga,Shani, Tom,Gottlieb, Hugo,Green, Omer,Shubely, Moran,Senderowitz, Hanoch,Israelson, Adrian,Kwon, Inchan,Petri, Susanne,Offen, Daniel,Gruzman, Arie
, p. 850 - 861 (2015/05/05)
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons and skeletal muscle atrophy. The majority of ALS cases are acquired spontaneously, with inherited disease accounting for only 10 % of all cases. Recent studies provide compelling evidence that aggregates of misfolded proteins underlie both types of ALS. Small molecules such as artificial chaperones can prevent or even reverse the aggregation of proteins associated with various human diseases. However, their very high active concentration (micromolar range) severely limits their utility as drugs. We synthesized several ester and amide derivatives of chemical chaperones. The lead compound 14, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethylpropan-1-amine oxide shows, in the micromolar concentration range, both neuronal and astrocyte protective effects in vitro; at daily doses of 10 mg kg-1 14 improved the neurological functions and delayed body weight loss in ALS mice. Members of this new chemical chaperone derivative class are strong candidates for the development of new drugs for ALS patients.
Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity
Kasibhatla, Srinivas R.,Hong, Kevin,Biamonte, Marco A.,Busch, David J.,Karjian, Patricia L.,Sensintaffar, John L.,Kamal, Adeela,Lough, Rachel E.,Brekken, John,Lundgren, Karen,Grecko, Roy,Timony, Gregg A.,Ran, Yingqing,Mansfield, Robert,Fritz, Lawrence C.,Ulm, Edgar,Burrows, Francis J.,Boehm, Marcus F.
, p. 2767 - 2778 (2008/02/06)
Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin- 2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 μM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 μM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17- desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.
Structure-activity relationship of 2-[[(2-Pyridyl)methyl]thio]-1H- benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy
Kühler, Thomas C.,Swanson, Marianne,Shcherbuchin, Vladimir,Larsson, H?kan,Mellg?rd, Bj?rn,Sj?str?m, Jan-Eric
, p. 1777 - 1788 (2007/10/03)
A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]- 1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 μg/mL. The structure - activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds 'that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]3-methyl-2-pyridyl)methyl]thio]-1H- benzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felis model (125 μmol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to the corresponding methyl sulfinyl derivative, i.e., a proton pump inhibitor, in vivo. Although the antibacterial activity had the potential of decreasing H. felis cell counts in vivo the proton pump inhibitory effect became dominant and actually promoted H. felis cell growth. Hence, we conclude that the antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]1H-benzimidazoles (6) as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.
