Lessons Learned from Marketed and Investigational Prodrugs

Ettmayer, Peter; Amidon, Gordon L.; Clement, Bernd; Testa, Bernard

doi:10.1021/jm0303812

Cited by 348 publications

(191 citation statements)

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“…In this regard, molecules which do not have suitable physicochemical properties would not overcome any of those three phases, limiting their use in clinical practice (1)(2)(3)(4). The main goal of pharmaceutical industries, nowadays, is to discover new, safe, effective, and orally administered chemical entities.…”

Section: Introductionmentioning

confidence: 99%

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

et al. 2014

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-Purpose. Prodrug design is a strategy that can be used to adjust physicochemical properties of drugs in order to overcome pharmacokinetic problems, such as poor oral bioavailability. However, Lipinski´s and Veber´s rules predict whether compounds will have absorption problems even before the design of prodrugs. In this context, our goal was to evaluate the molecular properties which most influenced the absorption process of prodrugs compared to its precursor through exploratory data analysis approach. Methods: A variety of prodrugs and respective precursors were randomly selected and classified by its' percentage of human intestinal absorption. Subsequently, different molecular properties were calculated and hierarchical cluster analysis (HCA) and principal components analysis (PCA) were carried out. Results: According to the findings, antiviral, anti-hypertensive, and antibiotic prodrugs exhibited higher absorption levels than their respective precursors. Also, some relevant descriptors (molecular weight, MW, routable bonds, rot_bonds, hydrogen bond acceptors, HBA_count and polar surface area, PSA), which are included in Lipinski´s and Veber´s rules, influenced the separation process between prodrugs and drugs. Furthermore, other molecular properties, such as polarizability (α) and molar refractivity (MR), were pointed out. Conclusion: Lipinski´s and Veber´s rules proved to be important to design an orally administered drug but other descriptors should be considered by medicinal chemists in the prodrug designing process.

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Section: Introductionmentioning

confidence: 99%

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

et al. 2014

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“…We chose to start from the new 23-phosphoramidite building block 3 (Scheme 1) which could be transformed into a series of conjugates using a solution-phase parallel array protocol, exploiting standard and reliable phosphoramidite chemistry. 15 We initially converted silybin (1) into its 23-ODMT ether by a reaction with DMT-chloride in pyridine at 50°C. After exhaustive acetylation with an excess of acetic anhydride in pyridine, subsequent treatment with 5% formic acid in dichloromethane allowed the removal of the DMT protecting group to give 2 in 75% yield and this could be converted into the corresponding phosphoramidite derivatives 3.…”

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confidence: 99%

“…In principle, this methodology can be readily extended to other molecules which have a free hydroxyl group. 15,28 …”

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confidence: 99%

“…The introduction of a phosphate group may bring pharmaceutical and pharmacokinetic benefits. 15 Conjugation is usually considered as an efficient route in drug discovery to improve the biological properties of a large number of drugs and can improve the bioavailability and delivery as well as the biological activity. We chose to start from the new 23-phosphoramidite building block 3 (Scheme 1) which could be transformed into a series of conjugates using a solution-phase parallel array protocol, exploiting standard and reliable phosphoramidite chemistry.…”

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New Silybin Scaffold for Chemical Diversification: Synthesis of Novel 23-Phosphodiester Silybin Conjugates

Zarrelli

Romanucci

Greca

et al. 2012

Synlett

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Silybin is the major component (ca. 30%) of the silymarin complex extracted from the seeds of Silybum marianum, with multiple biological activities operating at various cell levels. As an ongoing effort toward the exploitation of natural products as scaffolds for chemical diversification at readily accessible positions, we present here an efficient synthetic procedure to obtain new 23-phosphodiester silybin conjugates with different labels. A key point in our approach is the new 3,5,7,20-tetra-O-acetylsilybin-23-phosphoramidite, useful for a variety of derivatizations following a reliable and well-known chemistry. The feasibility of the procedure has been demonstrated by preparing new 23-silybin conjugates, exploiting standard phosphoramidite chemistry.Key words: natural products, flavonolignans, silybin, phosphorylation, drugs Flavonoids and flavonolignans are widely distributed among various citrus plants and are frequently found in the human diet. They may act as enzyme inhibitors, freeradical scavengers, antitumor agents, antibacterial agents, anti-inflammatory agents, and antioxidants. [1][2][3] Silybin (Figure 1) is the major component (ca. 30%) of the silymarin complex extracted from the seeds of Silybum marianum consisting of two diastereomers A and B in a ratio of approximately 1:1. Silybin is a natural compound with multiple biological activities operating at various cell levels most of them related to its radical-scavenging activity. Along with the beneficial activities resulting from the antioxidant and radical-scavenging properties, 3,4 silybin has recently received attention due to its anticancer and chemopreventive actions, 5,6 as well as hypocholesterolemic, cardioprotective, and neuroprotective activities. 3,7 In vivo applications of silybin are rather hampered by its very low bioavailability. In an attempt to improve its biological properties and facilitate in vivo applications of silybin, only limited structural modifications have been proposed 3,[8][9][10][11][12] and the available analogues are still unsatisfactory. Therefore new synthetic approaches for selectively modifying silybin are of interest. As a part of our continuing research effort towards the synthesis of new natural product analogues, 13,14 we present here the preliminary results of a efficient synthetic procedure to obtain new 23-phosphodiester silybin conjugates with different labels. The introduction of a phosphate group may bring pharmaceutical and pharmacokinetic benefits. 15 Conjugation is usually considered as an efficient route in drug discovery to improve the biological properties of a large number of drugs and can improve the bioavailability and delivery as well as the biological activity. We chose to start from the new 23-phosphoramidite building block 3 (Scheme 1) which could be transformed into a series of conjugates using a solution-phase parallel array protocol, exploiting standard and reliable phosphoramidite chemistry. 15 We initially converted silybin (1) into its 23-ODMT ether by a reaction with DMT...

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“…Em casos de multirresistência, alterações hepáticas e intolerância utiliza-se outros esquemas nos quais se variam os quimioterápicos (MENDES, FENSTERSEIFER, 2004;MINISTÉRIO DA SAÚDE, 2002WHO, 2010b;WONG, COHEN, BISHAI, 2013 (2005) A latenciação é uma estratégia que tem por finalidade otimizar as propriedades de uma molécula ativa, propriedades estas consideradas como fatores limitantes para sua utilização, tornando-a um fármaco passível de ser utilizado clinicamente. Como exemplo das referidas propriedades, podem-se citar problemas farmacocinéticos, ação inespecífica, elevada toxicidade, baixa estabilidade química, odor e paladar inadequados, dor no local de administração e dificuldade no preparo da forma farmacêutica (WERMUTH, 2008;ETTMAYER et al, 2004;CHUNG et al, 2005).…”

Section: Leishmanioseunclassified

Candidatos a leishmanicidas, antichagásicos e tuberculostáticos: estudo da síntese de fármacos dirigidos de hidroximetilnitrofural com manana para liberação específica em macrófagos

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Lessons Learned from Marketed and Investigational Prodrugs

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 348 publications

References 69 publications

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

New Silybin Scaffold for Chemical Diversification: Synthesis of Novel 23-Phosphodiester Silybin Conjugates

Candidatos a leishmanicidas, antichagásicos e tuberculostáticos: estudo da síntese de fármacos dirigidos de hidroximetilnitrofural com manana para liberação específica em macrófagos

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