TS-ANALOG

MOLECULAR DESIGN OF NOVEL PHARMACEUTICAL COMPOUNDS BASED ON TRANSITION STATE STRUCTURES ACCESSED VIA KINETIC ISOTOPE EFFECTS: AN EXPERIMENTAL AND THEORETICAL STUDY

Coordinatore	CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE    more  Organization address address: Rue Michel -Ange 3 city: PARIS postcode: 75794 contact info Titolo: Ms. Nome: Florence Cognome: Morineau Email: send email Telefono: + 33 2 99 28 68 12 Fax: + 33 2 99 28 68 03
Nazionalità Coordinatore	France [FR]
Totale costo	163˙643 €
EC contributo	163˙643 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2007-2-1-IEF
Funding Scheme	MC-IEF
Anno di inizio	2008
Periodo (anno-mese-giorno)	2008-04-15   -   2010-08-14

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE  Organization address address: Rue Michel -Ange 3 city: PARIS postcode: 75794 contact info Titolo: Ms. Nome: Florence Cognome: Morineau Email: send email Telefono: + 33 2 99 28 68 12 Fax: + 33 2 99 28 68 03	FR (PARIS)	coordinator	0.00

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 Obiettivo del progetto (Objective)

'This project will contribute towards the molecular design of analogues of transition state structures associated with the degradation of therapeuticals. It will train an essentially computational chemist in experimental techniques, allowing her to become an independent research with broad experience in isotopic studies. The specific experimental training objective of the project is the determination of kinetic isotope effects to interpret the reaction mechanisms of degradation. This will require the synthesis of isotopically-labelled target compounds and the study of their metabolism in vitro in mammalian and bacterial cell cultures. The project is an integral part of a programme researching the molecular mechanisms associated with the metabolism of therapeutic agents and their improvement through enhanced stability. It will focus on nicotine- and tropine-based compounds that are currently medicaments or are in evaluation as potential medicaments. These have a wide range of therapeutic activities: control of tobacco dependency; alleviation of addiction; treatment of neurodegenerative diseases; muscle relaxants. Instability of bioactive compounds presents a serious problem in drug design. The response adopted is frequently the use of higher doses, often associated with deleterious side-effects. A better understanding of the pharmacokinetics can allow a lower dose to be prescribed. Degradation often involves a dominant role for cytochrome P450-dependent oxidases through N-demethylation, oxidation, or ring cleavage. Improved resistance by structural modification or the use of a specific inhibitor will lead to improved therapy. The Host Laboratory has a strong experience in the experimental determination of isotopes in natural products by mass and NMR spectrometries. Acquiring these skills will complement the established abilities of the Researcher in the molecular modelling of reaction intermediates and transition states by in silico calculations of isotope effects.'