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Rouen, France

Barre A.,INSA Rouen | Tintas M.-L.,INSA Rouen | Alix F.,VFP Therapies | Gembus V.,VFP Therapies | And 2 more authors.
Journal of Organic Chemistry | Year: 2015

An efficient Pd-catalyzed carbonylation protocol is described for the coupling of a large panel of aryl, heteroaryl, benzyl, vinyl and allyl halides 2 with the unusual N-hydroxysuccinimidyl (NHS) formate 1 as a CO surrogate to afford the corresponding valuable NHS esters 3. High conversion to the coupling products was achieved with up to 98% yield by means of Pd(OAc)2/Xantphos catalyst system. © 2015 American Chemical Society. Source


Patent
INSA Rouen, French National Center for Scientific Research, University of Rouen and Vfp Therapies | Date: 2014-01-24

A compound of formula (I) in which the dotted lines indicate the presence of at least one double bond; n=0 to 4; R


Bohn P.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Gourand F.,French Atomic Energy Commission | Papamicael C.,CNRS Organic Chemistry, Bioorganic Chemistry: Reactivity and Analysis | Ibazizene M.,French Atomic Energy Commission | And 7 more authors.
ACS Chemical Neuroscience | Year: 2015

With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biological evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug 1a [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug 2a [IC50 = 20 nM (hAChE)] through central redox activation of 1a. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent positive charge in 2a promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug 1a was developed for additional ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [11C]1a, while identification of [11C]2a and [11C]3a both accounts for central redox activation of 1a and pseudoirreversible inhibition of AChE, respectively. Finally, Caco-2 permeability assays predicted metabolite 3a as a substrate for efflux transporters (P-gp inter alia), suggesting that metabolite 3a might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors. © 2015 American Chemical Society. Source

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