flatfish
11-01-2006, 01:28 PM
##################### Bovine Spongiform Encephalopathy #####################
A Potential Anti-prion Drug With 'Unprecedented' Potency
The urgent search for a medication to treat prion diseases has led scientists in Germany to synthesize a new group of compounds, including one that is 15 times more potent than an approved drug now being tested in clinical trials.
Their report is scheduled for the Nov. 2 issue of the biweekly ACS Journal of Medicinal Chemistry.
Prions are infectious proteins that cause brain disorders like Mad Cow Disease and Creutzfeldt-Jakob Disease (CJD) in humans. Peter Gmeiner and colleagues note that the recent emergence of a new form of CDJ, linked to consumption of infected beef mainly in Great Britain, intensified the search for anti-prion compounds.
Most potential drugs have proved ineffective, often because they could not enter brain tissue where prions reside. One promising drug, however, is in clinical trials. That drug is quinacrine, already approved for several other medical conditions.
Gmeiner's group describes the chemical synthesis and early laboratory testing of a family of anti-prion compounds that cross into brain tissue and combat prions. One of those compounds has what the report describes as "unprecedented" anti-prion activity, with 15 times greater potency than quinacrine.
http://www.sciencedaily.com/releases/2006/10/061030120759.htm
J. Med. Chem., 49 (22), 6591 -6595, 2006. 10.1021/jm060773j S0022-2623(06)00773-4
Web Release Date: September 29, 2006
Copyright © 2006 American Chemical Society
A Chimeric Ligand Approach Leading to Potent Antiprion Active Acridine Derivatives: Design, Synthesis, and Biological Investigations
Silke Dollinger, Stefan Löber, Ralf Klingenstein, Carsten Korth, and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany, and Institute for Neuropathology, Medical School, Heinrich Heine University Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany
Received June 29, 2006
Abstract:
Human transmissible neurodegenerations including Creutzfeldt-Jakob disease are unique, since they are caused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversion of a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy of these unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but with ambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine and iminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structural chimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of a focused library of these compounds. The most potent target compound 2a revealed an EC50 value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2006/49/i22/abs/jm060773j.html
Introduction
Prion diseases are transmissible neurodegenerative diseases
of humans and animals.1 The prion agent replicates without a
nucleic acid-encoded genome by converting host-resident normal
prion protein (PrPC)a to a pathogenic and infectious conformational
isoform PrPSc. Human prion diseases such as the most
prevalent Creutzfeldt-Jakob disease (CJD) are rare diseases that
cansuniquelysbe of sporadic, genetic, or infectious origin.
Animal prion diseases are almost exclusively infectious in origin
in the form of scrapie of sheep, bovine spongiform encephalopathy
(BSE) or mad cow disease of cattle, or chronic wasting
disease of American mule deer or elk. The emergence of a new
strain of human prions causing variant CJD (vCJD) through
the consumption of BSE-contaminated material 2 led to 160
deaths, primarily in Great Britain, and to concerns of an epidemy
of vCJD which, so far, has neither happened nor been
completely excluded.3 The new vCJD strain has different
characteristics, such as the occurrence of infectivity in blood
and peripheral organs, which increases the risk of horizontal
transmission, for example, during blood transfusions.4 These
issues have led to a focus on pharmacotherapeutic options of
prion diseases both for symptomatic, curative, and prophylactic
purposes or for decontamination of blood and transplanted
organs.
Although screening for antiprion compounds in scrapieinfected
mouse neuroblastoma cells (ScN2a) as a cell culture
model of prion disease has led to the identification of many
antiprion compounds, most of them proved to be ineffective
when applied to experimentally prion-infected rodents owing
to the lack of blood-brain barrier (BBB) permeability or
toxicity.5 The identification of BBB-permeable heterocyclic
compounds sparked a tremendous effort to enter clinical trials
applying the approved drug quinacrine to patients with CJD.6
Since animal experiments with quinacrine gave only modest or
ambiguous results,7 quinacrine pharmacotherapy could be
improved by introducing a combination of antiprion drugs.8
Structural modifications employing quinacrine as a lead compound
revealed that bis-acridines augmented antiprion activity
around 10-fold in vitro,9 but poor solubility is likely to limit
their in vivo use. The synergistic antiprion effects of quinacrineand
iminodibenzyl-derived antidepressants have prompted us
to synthesize heterodimers incorporating both recognition elements
with a piperazine unit,10 which is known as a privileged
substructure in a great number of bioactive agents, as the linking
element.
On the basis of preliminary investigations on the hybrid 1
(Figure 1) displaying a 5-fold improved antiprion potency over
quinacrine,8 we herein describe a novel class of antiprion agents
of type 2 defined by covalently linked acridine and iminodibenzyl
moieties and variations of the particular molecular
subunits. SAR studies led to the discovery of the iminodibenzyl
derivative 2a as the most active antiprion compound yet
described.
Chemistry. ...SNIP...FULL TEXT ;
http://pubs.acs.org/cgi-bin/sample.cgi/jmcmar/2006/49/i22/pdf/jm060773j.pdf
TSS
#################### https://lists.aegee.org/bse-l.html ####################
quinacrine has failed to ever cure anyone from cjd, and one side effect seems to be to turn the person taking the substance yellow. maybe this new cocktail will prove to be benificial. we can only hope so. ...TSS
A Potential Anti-prion Drug With 'Unprecedented' Potency
The urgent search for a medication to treat prion diseases has led scientists in Germany to synthesize a new group of compounds, including one that is 15 times more potent than an approved drug now being tested in clinical trials.
Their report is scheduled for the Nov. 2 issue of the biweekly ACS Journal of Medicinal Chemistry.
Prions are infectious proteins that cause brain disorders like Mad Cow Disease and Creutzfeldt-Jakob Disease (CJD) in humans. Peter Gmeiner and colleagues note that the recent emergence of a new form of CDJ, linked to consumption of infected beef mainly in Great Britain, intensified the search for anti-prion compounds.
Most potential drugs have proved ineffective, often because they could not enter brain tissue where prions reside. One promising drug, however, is in clinical trials. That drug is quinacrine, already approved for several other medical conditions.
Gmeiner's group describes the chemical synthesis and early laboratory testing of a family of anti-prion compounds that cross into brain tissue and combat prions. One of those compounds has what the report describes as "unprecedented" anti-prion activity, with 15 times greater potency than quinacrine.
http://www.sciencedaily.com/releases/2006/10/061030120759.htm
J. Med. Chem., 49 (22), 6591 -6595, 2006. 10.1021/jm060773j S0022-2623(06)00773-4
Web Release Date: September 29, 2006
Copyright © 2006 American Chemical Society
A Chimeric Ligand Approach Leading to Potent Antiprion Active Acridine Derivatives: Design, Synthesis, and Biological Investigations
Silke Dollinger, Stefan Löber, Ralf Klingenstein, Carsten Korth, and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany, and Institute for Neuropathology, Medical School, Heinrich Heine University Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany
Received June 29, 2006
Abstract:
Human transmissible neurodegenerations including Creutzfeldt-Jakob disease are unique, since they are caused by prions, an infectious agent that replicates without nucleic acids but instead by inducing conversion of a host-resident normal prion protein to a misfolded conformational isoform. For pharmacotherapy of these unusual diseases, tricyclic heterocyclic compounds such as quinacrine have been considered, but with ambiguous success in vivo, so far. On the basis of the synergistic antiprion effects of quinacrine and iminodibenzyl derivatives, we introduce a novel class of potential pharmaceuticals representing structural chimeras of quinacrine and imipramine analogues. We describe the chemical synthesis and bioassays of a focused library of these compounds. The most potent target compound 2a revealed an EC50 value of 20 nM determined with a cell model of prion disease, thus substantially improving the antiprion efficacy of quinacrine.
http://pubs.acs.org/cgi-bin/abstract.cgi/jmcmar/2006/49/i22/abs/jm060773j.html
Introduction
Prion diseases are transmissible neurodegenerative diseases
of humans and animals.1 The prion agent replicates without a
nucleic acid-encoded genome by converting host-resident normal
prion protein (PrPC)a to a pathogenic and infectious conformational
isoform PrPSc. Human prion diseases such as the most
prevalent Creutzfeldt-Jakob disease (CJD) are rare diseases that
cansuniquelysbe of sporadic, genetic, or infectious origin.
Animal prion diseases are almost exclusively infectious in origin
in the form of scrapie of sheep, bovine spongiform encephalopathy
(BSE) or mad cow disease of cattle, or chronic wasting
disease of American mule deer or elk. The emergence of a new
strain of human prions causing variant CJD (vCJD) through
the consumption of BSE-contaminated material 2 led to 160
deaths, primarily in Great Britain, and to concerns of an epidemy
of vCJD which, so far, has neither happened nor been
completely excluded.3 The new vCJD strain has different
characteristics, such as the occurrence of infectivity in blood
and peripheral organs, which increases the risk of horizontal
transmission, for example, during blood transfusions.4 These
issues have led to a focus on pharmacotherapeutic options of
prion diseases both for symptomatic, curative, and prophylactic
purposes or for decontamination of blood and transplanted
organs.
Although screening for antiprion compounds in scrapieinfected
mouse neuroblastoma cells (ScN2a) as a cell culture
model of prion disease has led to the identification of many
antiprion compounds, most of them proved to be ineffective
when applied to experimentally prion-infected rodents owing
to the lack of blood-brain barrier (BBB) permeability or
toxicity.5 The identification of BBB-permeable heterocyclic
compounds sparked a tremendous effort to enter clinical trials
applying the approved drug quinacrine to patients with CJD.6
Since animal experiments with quinacrine gave only modest or
ambiguous results,7 quinacrine pharmacotherapy could be
improved by introducing a combination of antiprion drugs.8
Structural modifications employing quinacrine as a lead compound
revealed that bis-acridines augmented antiprion activity
around 10-fold in vitro,9 but poor solubility is likely to limit
their in vivo use. The synergistic antiprion effects of quinacrineand
iminodibenzyl-derived antidepressants have prompted us
to synthesize heterodimers incorporating both recognition elements
with a piperazine unit,10 which is known as a privileged
substructure in a great number of bioactive agents, as the linking
element.
On the basis of preliminary investigations on the hybrid 1
(Figure 1) displaying a 5-fold improved antiprion potency over
quinacrine,8 we herein describe a novel class of antiprion agents
of type 2 defined by covalently linked acridine and iminodibenzyl
moieties and variations of the particular molecular
subunits. SAR studies led to the discovery of the iminodibenzyl
derivative 2a as the most active antiprion compound yet
described.
Chemistry. ...SNIP...FULL TEXT ;
http://pubs.acs.org/cgi-bin/sample.cgi/jmcmar/2006/49/i22/pdf/jm060773j.pdf
TSS
#################### https://lists.aegee.org/bse-l.html ####################
quinacrine has failed to ever cure anyone from cjd, and one side effect seems to be to turn the person taking the substance yellow. maybe this new cocktail will prove to be benificial. we can only hope so. ...TSS