Article

Novel Prodrug Approach for Tertiary Amines:  Synthesis and Preliminary Evaluation of N-Phosphonooxymethyl Prodrugs

Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
Journal of Medicinal Chemistry (impact factor: 5.25). 07/1999; 42(16). DOI:10.1021/jm980539w

ABSTRACT The synthesis and preliminary evaluation of a novel prodrug approach for improving the water solubility of drugs containing a tertiary amine group are reported. The prodrug synthesis involves a nucleophilic substitution reaction between the parent tertiary amine and a novel derivatizing reagent, di-tert-butyl chloromethyl phosphate, resulting in formation of the quaternary salt. The tertiary butyl groups are easily removed under acidic conditions with trifluoroacetic acid giving the N-phosphonooxymethyl prodrug in the free phosphoric acid form, which can subsequently be converted to the desired salt form. The synthesis was successfully applied to a model compound (quinuclidine) and to three tertiary amine-containing drugs (cinnarizine, loxapine, and amiodarone). The prodrugs were designed to undergo a two-step bioreversion process. The first step was an enzyme-catalyzed rate-determining dephosphorylation followed by spontaneous chemical breakdown of the N-hydroxymethyl intermediate to give the parent drug. Selected prodrugs were shown to be substrates for alkaline phosphatase in vitro. A preliminary in vivo study confirmed the ability of the cinnarizine prodrug to be rapidly and completely converted to cinnarizine in a beagle dog following iv administration.

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    Article: Prodrugs for the treatment of neglected diseases.
    Man Chin Chung, Elizabeth Igne Ferreira, Jean Leandro Santos, Jeanine Giarolla, Daniela Gonçales Rando, Adélia Emília Almeida, Priscila Longhin Bosquesi, Renato Farina Menegon, Lorena Blau
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    ABSTRACT: Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people,mainly in developing countries, die each year from infectious diseases. From 1975 to 1999,1393 new drugs were approved yet only 1% were for the treatment of neglected diseases[3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas' disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.
    Molecules 01/2008; 13(3):616-77. · 2.39 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

acidic conditions
 
beagle dog
 
cinnarizine prodrug
 
desired salt form
 
di-tert-butyl chloromethyl phosphate
 
enzyme-catalyzed rate-determining dephosphorylation
 
first step
 
free phosphoric acid form
 
iv administration
 
N-phosphonooxymethyl prodrug
 
novel derivatizing reagent
 
novel prodrug approach
 
nucleophilic substitution reaction
 
parent tertiary amine
 
preliminary evaluation
 
quaternary salt
 
spontaneous chemical breakdown
 
tertiary butyl groups
 
two-step bioreversion process
 
vivo study