Single Chemical Entity Research Articles

A divergent route towards single-chemical entity triazine dendrimers with opportunities for structural diversity

This manuscript describes the successful synthesis and characterization of five generations of dendrimers based on melamine. Early generations of these materials appear to be single chemical entities: upon purification, no detectable impurities are observed using NMR spectroscopy, mass spectrometry, and HPLC and GPC analysis. The analysis of larger generation materials precludes an unambiguous statement of purity. The synthetic route to these targets is divergent, relying on dichlorotriazine monomers that react with a polyamine dendrimer core of generation n to produce a poly(monochlorotriazine) dendrimer of generation n + 1. Subsequently, the poly(monochlorotriazine) is derivatized through nucleophilic aromatic substitution before additional nucleophilic amines are unmasked and the process iterated.

The Multiple Amidation Reactions Catalyzed by Cobyric Acid Synthetase from Salmonella typhimurium Are Sequential and Dissociative

The biosynthesis of coenzyme B12 is a complex process involving more than two dozen enzymatic reactions. Near the end of this biosynthetic pathway cobyric acid synthetase (CbiP) catalyzes the remarkable amidation of four separate carboxylate groups within a single substrate, adenosyl-cobyrinic acid a,c-diamide. The time course for the multiple amidation reactions demonstrates that the partially amidated products are released from the active site after every round of catalysis, and thus the mechanism of the reaction is dissociative. The partially amidated intermediates were shown to be single chemical entities demonstrating that the four carboxylate groups are amidated in a specific reaction sequence. NMR spectroscopy was used to establish that carboxylate e was the first to be amidated followed in turn by d, b, and g. These results indicate that the initial substrate can productively bind to the enzyme active site in only one of four possible orientations. After the amidation of carboxylate e, the first p...

Monitoring anticoagulation by fondaparinux: determination of anti factor Xa-level

In contrast to low molecular weight heparin and unfractionated heparin fondaparinux is a selective synthetic factor Xa inhibitor. It was approved for thromboprophylaxis after major orthopaedic surgery three years ago. Because of its excellent bioavailability after subcutaneous application once daily independent of body weight (within the range of 50-100 kg) monitoring of the substance is usually not necessary. Since its recent approval for therapeutic use in acute venous thrombosis monitoring might be useful in special clinical situations (e. g. suspected over- or underdosing, renal insufficiency or severe bleeding complications). Based on standard laboratory methods for the chromogenic determination of the anti-factor Xa activity of low molecular weight heparin several chromogenic substrate assays were published for monitoring. Only fondaparinux should be used for calibration and measured fondaparinux levels should be expressed in mug/ml of the fondaparinux calibrator. Because of its single synthetic chemical entity, a linear dose/response relationship over a wide concentration range is observed and measurements are of high precision.

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Herb–drug interactions: an overview of the clinical evidence

Herbal medicines are mixtures of more than one active ingredient. The multitude of pharmacologically active compounds obviously increases the likelihood of interactions taking place. Hence, the likelihood of herb-drug interactions is theoretically higher than drug-drug interactions, if only because synthetic drugs usually contain single chemical entities. Case reports and clinical studies have highlighted the existence of a number of clinically important interactions, although cause-and-effect relationships have not always been established. Herbs and drugs may interact either pharmacokinetically or pharmacodynamically. Through induction of cytochrome P450 enzymes and/or P-glycoprotein, some herbal products (e.g. St John's wort) have been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of conventional drugs, including cyclosporine, indinavir, irinotecan, nevirapine, oral contraceptives and digoxin. The majority of such interactions involves medicines that require regular monitoring of blood levels. To date there is less evidence relating to the pharmacodynamic interaction. However, for many of the interactions discussed here, the understanding of the mechanisms involved is incomplete. Taking herbal agents may represent a potential risk to patients under conventional pharmacotherapy.

Überwachung der Antikoagulanzientherapie mit Fondaparinux

ZusammenfassungIm Gegensatz zu niedermolekularem und unfraktioniertem Heparin besitzt Fondaparinux, ein synthetisch hergestelltes Pentasaccharid, einen selektiv hemmenden Effekt auf den Gerinnungsfaktor X. Die Substanz ist seit drei Jahren zur Hochrisikothromboseprophylaxe nach großen orthopädischen Operationen zugelassen. Auf Grund der ausgezeichneten Bioverfügbarkeit nach subkutaner Gabe, die einmal pro Tag in körpergewichtsunabhängiger Dosierung (bei einem Körpergewicht von 50-100 kg) erfolgen kann, ist normalerweise ein Monitoring nicht erforderlich. Insbesondere seit der europaweiten Zulassung zur Therapie venöser Thrombosen ist jedoch im Ausnahmefall (z. B. Verdacht auf Fehldosierung, bei Niereninsuffizienz oder Blutungen) ein Monitoring im Routinelabor sinnvoll.Inzwischen wurden chromogene Substratmethoden, basierend auf zur Verfügung stehenden Monitoring-Methoden zur Messung des Faktor Xa inhibierenden Effektes der niedermolekularen Heparine, publiziert. Unter Berücksichtigung dieser Publikationen sollte Fondaparinux als Kalibrator verwendet und die Einheiten in μg/ml angegeben werden. Wegen der synthetischen Herstellung der Substanz findet sich eine lineare Dosis/Wirkungsbeziehung in einem weiten Konzentrationsbereich, so dass eine sehr gute Präzision der Methodik an Vollautomaten erreicht werden kann.

Plants as a Source of Bacterial Resistance Modulators and Anti-Infective Agents

The spread of multidrug-resistant (MDR) strains of bacteria necessitates the discovery of new classes of antibacterials and compounds that inhibit these resistance mechanisms. At present, there are no single chemical entity plant-derived antibacterials used clinically, and this chemically diverse group deserves consideration as a source for two major reasons. First, plants have exceptional ability to produce cytotoxic agents and second there is an ecological rationale that antimicrobial natural products should be present or synthesised de novo in plants following microbial attack to protect the producer from pathogenic microbes in its environment. We have been characterising plant-derived products that are either antibacterial in their own right, or modulators of resistance in bacterial strains possessing multidrug efflux mechanisms. These efflux transporters are responsible for resistance to certain antibiotics and antiseptics and occur in strains of methicillin-resistant Staphylococcus aureus (MRSA), a major clinical problem at present. We are also investigating plant sources for compounds with activity against mycobacteria with a view to discovering drug leads with potential activity toward tuberculosis (TB) producing species. This paper will briefly review the literature on plant derived bacterial resistance modifying agents and antibacterials. Examples in this area from our own work will be given. The activities of plant-derived antibacterials show that there are many potential new classes of antibacterial agents which should undergo further cytotoxicity, microbial specificity and preclinical studies.

Multicomponent therapeutics for networked systems

Therapeutic regimens that comprise more than one active ingredient are commonly used in clinical medicine. Despite this, most drug discovery efforts search for drugs that are composed of a single chemical entity. A focus in the early drug discovery process on identifying and optimizing the activity of combinations of molecules can result in the identification of more effective drug regimens. A systems perspective facilitates an understanding of the mechanism of action of such drug combinations.

Quantitative 1H NMR: Development and Potential of a Method for Natural Products Analysis

Based on a brief revision of what constitutes state-of-the-art "quantitative experimental conditions" for (1)H quantitative NMR (qHNMR), this comprehensive review contains almost 200 references and covers the literature since 1982 with emphasis on natural products. It provides an overview of the background and applications of qHNMR in natural products research, new methods such as decoupling and hyphenation, and analytical potential and limitations, and compiles information on reference materials used for and studied by qHNMR. The dual status of natural products, being single chemical entities and valuable biologically active agents that need to be purified from complex matrixes, results in an increased analytical demand when testing their deviation from the singleton composition ideal. The outcome and versatility of reported applications lead to the conclusion that qHNMR is currently the principal analytical method to meet this demand. Considering both 1D and 2D (1)H NMR experiments, qHNMR has proved to be highly suitable for the simultaneous selective recognition and quantitative determination of metabolites in complex biological matrixes. This is manifested by the prior publication of over 80 reports on applications involving the quantitation of single natural products in plant extracts, dietary materials, and materials representing different metabolic stages of (micro)organisms. In summary, qHNMR has great potential as an analytical tool in both the discovery of new bioactive natural products and the field of metabolome analysis.

The rediscovery of ancient Chinese herbal formulas.

This review presents some recent discoveries of ancient Chinese herbal formulas evolved through thousands of years of clinical practice. It appears that many of the ancient combination formulas have sound scientific basis through modern pharmacological evaluation. Significant chemical changes occurred during the preparation (decoction) process of a prescribed herbal formula. For example, some toxic ingredients were significantly reduced and new active compounds generated due to the chemical interactions among the ingredients. Many combination formulas showed significantly better pharmacological results than individual herbal medicines participated in the formula. These findings suggest that the current drug screening and regulatory methodology will not be appropriate for the development of a botanical drug containing a group of phytochemicals, in which a synergistic interaction from chemical ingredients plays a fundamental role in the treatment of disease. If we view a diseased state in a holistic and dynamic way, i.e. it involves interactions among many biological systems in human body and these interactions change as the disease improves or worsens, the treatment of such disease with a single chemical entity may not be logical or technically feasible. Combination formulas may hold the potential to become the therapeutics of choice in the future due to the synergistic effect and dynamic adjustment achieved by the multiple ingredients that will restore the balance of an imbalanced or diseased human body.

Anti‐Staphylococcal Plant Natural Products

AbstractFor Abstract see ChemInform Abstract in Full Text.

Dynamic competition in pharmaceuticals. Patent expiry, generic penetration, and industry structure.

This paper investigates patterns of industrial dynamics and competition in the pharmaceutical industry, with particular reference to the consequences of patent expiry in different countries. We focus on the competition at the level of single chemical entities, distinguishing between original brands and generic products. Quarterly data, spanning from July 1987 to December 1998, on sales of pharmaceutical products in four countries (USA, UK, Germany, and France) constitute the basis of our analysis. All the products containing major molecules whose patent expiration date lies between 1986 and 1996 are included in our sample. We show how diffusion of generics is linked to the characteristics of the market and investigate how price dynamics of original products are affected by generic competition. Our empirical investigation shows that the dynamics of drug prices and the competition by generic drugs vary significantly across countries. This heterogeneity notwithstanding, a clear distinction seems to emerge. On the one hand, systems that rely on market-based competition in pharmaceuticals promote a clear distinction between firms that act as innovators and firms that act as imitators after patent expiry. Here, original products enjoy premium prices and exclusivity profits under patent protection, and face fierce price competition after patent expiry. On the other hand, in systems that rely on administered prices, penetration by generic drugs tends to be rather limited. Its descriptive and preliminary nature notwithstanding, our analysis seems to have relevant implications at different levels of generality, especially for Europe.

Anti-staphylococcal plant natural products.

Covering: 1995 to 2003 The occurrence of vancomycin-resistant Staphylococcus aureus (VRSA) and multidrug-resistant (MDR) strains of this organism necessitate the discovery of new classes of anti-staphylococcal drug leads. At present there are no single chemical entity plant derived antibacterials used clinically, and this biologically diverse group deserves consideration as a source of chemical diversity for two important reasons. Firstly, plants have exceptional ability to produce cytotoxic agents and, secondly, there is an ecological rationale that antibacterial natural products should be present or synthesised de novo following microbial attack to protect plants from invasive and pathogenic microbes in their environment. This review cites plant natural products that either modify resistance in Staphylococcus aureus or are antibacterial through bacteriostatic or bactericidal properties. The activities described here show that there are many potential new classes of anti-staphylococcal agents which should undergo further cytotoxicity, microbial specificity and preclinical in vivo studies to assess their potential.

Controlling the properties of single‐polymer composites by surface melting of the reinforcing fibers

AbstractAll‐thermoplastic single‐polymer composites are materials in which both the reinforcing fibrous phase and the matrix between them are made of the same thermoplastic polymer. Excellent bonding is achieved by mutual entanglement macromolecules due to controlled surface melting of the fibers. This results in a uniform structure of a single chemical entity. The physical properties of the consolidated material, such as modulus and coefficient of thermal expansion (CTE), can be controlled by the extent of melting effected in the process, which determines the fiber/matrix ratio. The fabrication technology utilizes oriented polymer fibers in various forms: unidirectional lay‐up, woven fabric or chopped fibers/non‐woven felt. The key element in the processing scheme is the control of the fibers' melting temperature by hydrostatic pressure. The fibers are heated under high pressure to a temperature that is below their melting point at the high pressure but above the melting temperature at some lower pressure. Reduction of pressure for controlled time results in melting of the fibers, which starts at the fiber surface. This surface melting under controlled pressure followed by crystallization produces the consolidated structure. We illustrate and describe this process using fibers of ultra‐high‐molecular‐weight polyethylene (UHMWPE), showing the effect of the processing conditions on the flexural modulus, fiber/matrix ratio, and CTE in plane and in the thickness direction. These properties are relevant to the use of such composites as substrates for microwave antennae. Copyright © 2003 John Wiley & Sons, Ltd.

The development of single-isomer molecules: why and how.

Until relatively recently the three-dimensional nature of drug molecules has been largely neglected, with approximately 25% of marketed drugs being mixtures of agents rather than single chemical entities. These mixtures are not combinations of drugs but mixtures of stereoisomers, generally racemates of synthetic chiral drugs. The individual enantiomers present in such mixtures frequently differ in both their pharmacodynamic and pharmacokinetic profiles as a result of stereochemical discrimination on interaction with chiral biological macromolecules (enzymes and receptors). The use of such mixtures may present problems if their adverse effects are associated with the less active stereoisomer or do not show stereoselectivity. In addition, interactions between enantiomers may occur such that the observed activity of the racemate is not simply the product of the effects of the individual enantiomers. Since the mid-1980s there has been an ongoing "racemate-versus-enantiomer" debate with the potential advantages of single-isomer products, including improved selectivity of action and potential increase in therapeutic index, being highlighted. As a result, regulatory authorities have issued guidelines for dealing with chiral molecules, and the number of single enantiomer agents presented for evaluation has increased. Racemic mixtures may still be developed but require justification such that the risk-benefit ratio may be assessed. In addition to new chemical entities, a number of "old" mixtures are being re-examined as potential single-isomer products, the chiral switches, with the potential for an improved therapeutic profile and possibly new indications. However, for the majority of agents currently marketed as mixtures, relatively little is known concerning the pharmacological or toxicological properties of the individual enantiomers.

Design and synthesis of a novel L-dopa-entacapone codrug.

A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate codrug provides adequate stability [t(1/2) = 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t(1/2) = 7 min; pH 7.4) at 37 degrees C. The therapeutical potential of this novel codrug is discussed.

Design of virtual combinatorial libraries.

AbstractLast year marked the completion of the sequencing effort on the human genome. Advances in the fields of genomics and bioinformatics are widely expected to bring forth a large number of new biochemical targets for drug design by linking specific diseases to single genes or collections thereof. The pharmaceutical and biotechnology sector is now likely to become one of the most active industrial fields in the new century. A dramatic increase in the number of pharmaceutical targets in the near future would create a bottleneck of sorts at the stage of pharmaceutical drug discovery. Historically, this field has used a serial process, screening and optimizing compounds one at a time. However, the advent of combinatorial chemistry and high-throughput screening has significantly altered the face of drug discovery. Rapid generation and screening of combinatorial libraries has become commonplace in both industry and academia; with the ever-growing offering of organic reagents along with the vast palette of organic reactions, the chemical space accessible to combinatorial chemists has dramatically expanded. The application of combinatorial technology, however, is not without a potential caveat—even as the cost of synthesis and testing of a single chemical entity has fallen, it skyrockets when multiplied by the thousands or millions of combinatorial library members. Some of the potential solutions include (i) use of the three-dimensional target structure information in the design process; (ii) application of pharmacophore and quantitative structure-activity relationship (QSAR) methods to focus on libraries that most closely resemble screening hits; and (iii) reduction in the scale on which both medicinal chemistry and screening are currently performed. These solutions imply a need for a rational approach to reducing library size, custom izing the library for a given target, and more efficient in silico screening of a library (or, potentially, multiple libraries) of compounds against a large number of targets of interest. The challenge in accomplishing these goals is in being able to reduce the library while increasing the potential hit rate of individual library members.KeywordsLibrary DesignVirtual LibraryMolar RefractivityLibrary MemberAvailable Chemical DirectoryThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Innovation and corporate growth in the evolution of the drug industry

This work studies the processes of growth of the worlds top 150 pharmaceutical firms, on the grounds of an original database which also allows disaggregate analysis at the level of single therapeutical classes and chemical entities. Our findings show that the industry — whose long-term evolution is driven by innovation, imitation and permanent creation of new markets — displays (i) “fat tails” in the distribution of growth shocks, present at all levels of aggregation, with (relatively rare) big “spurs of growth”, (ii) a significant autocorrelation of growth rates, (iii) a fall of variance of growth rates with size entirely dependent on corporate diversification patterns, in turn plausibly shaped by the “competence scope” of each firm, and (iv) different “lifecycles” of diverse types of products, and persistent forms of heterogeneity across firms in terms of innovative output, which, however, do not not seem to affect comparative growth performances.

Dietary intervention strategies: validity, execution and interpretation of outcomes.

Experimental research designs that use single chemical entities have been the cornerstone of careful scientific research. Therefore the use of total diet patterns, or whole foods, which contain hundreds of chemical components, would appear to lack sufficient control to yield productive information. However, cancer prevention and control may be an area where well-designed diet intervention strategies may be an efficient research approach. This chapter will present arguments for the necessity of diet and whole food supplementation research studies and descriptions of strategies for their implementation. Additionally, the components of effective diet intervention studies will be discussed. Whether the research involves cell media, animal diets or human diets, the whole diet should be considered an important factor in any research design where the ultimate aim is cancer prevention and control.

A receptor-specific peptide for imaging infection and inflammation.

The chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP), when radiolabelled, continues to be an attractive agent for imaging infection or inflammation. Previously, several analogues of fMLP have been prepared and radiolabelled using a bifunctional chelating agent conjugation procedure that was relatively long and complex. We have prepared a new analogue of fMLP, TP765, by the addition of 4-aminobutyric acid (4-ABA) and a group of four amino acids, Gly-Gly-d-Ala-Gly, to the carboxy terminus (i.e. to the phenylalanine) of fMLP. The adduct -(4-ABA)-Gly-Gly-d-Ala-Gly- serves as a chelating moiety for strong chelation with 99Tcm. The use of a peptide as a chelating moiety greatly simplified the synthetic procedure and rendered the analogue ready for instant chelation with 99Tcm. HPLC analysis revealed that 99Tcm-TP765 was a single chemical entity that retained biological activity and neutrophil specificity. 99Tcm-TP765 was stable when challenged with strong chelating agents in vitro and had rapid but biphasic blood clearance (alphat1/2 = 7 min, betat1/2 = 45 min). Approximately 90% of the radioactivity had cleared from circulation within 45 min post-injection and the agent had accumulated in experimental bacterial or sterile abscesses in significantly (P<0.05) higher quantities than the analogues evaluated previously. Generally, the biodistribution pattern of 99Tcm-TP765 was similar to that of other analogues examined and its abscess uptake was independent of the abscess age. In conclusion, a new analogue of fMLP, 99Tcm-TP765, was prepared by a simple procedure. This new analogue has properties similar to those of previously examined analogues used as agents for imaging infection or inflammation.