Synthetic approaches to the 2011 new drugs

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 26 NCEs that were launched in the world in 2011.     

Synthetic approaches to the 2010 new drugs

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010.     

Synthetic approaches to the 2014 new drugs

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.     

Synthetic approaches to the 2009 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.     

全球最有前景Ⅰ—Ⅲ期临床与获批上市新药Top5——2014 年第1 季度

介绍了2014 年第1 季度面市或获批以及分别进入Ⅲ、Ⅱ、Ⅰ期临床试验的最具前景的各5 个代表性药物，旨在为新药研发工作者提供参考。     

A meta‐analysis of non‐consumptive predator effects in arthropods: the influence of organismal and environmental characteristics

Non‐consumptive effects (NCEs) – changes in prey behavior or physiology in response to predator threat – are common and can be as strong as consumptive effects. However, our knowledge of NCEs in arthropod systems is lacking. Factors related to study organism and environment have the potential to influence the occurrence and magnitude of NCEs in arthropod systems. While factors such as coevolutionary history of natural enemies and their prey, predator cue, predator or prey feeding mode, and refuge availability have been theoretically and empirically examined, no trends have been proposed for arthropods. We compiled 62 studies, yielding 128 predator–prey interactions, which explicitly examined NCEs in experiments where arthropods were identified to species, using a previously published database of papers from 1990 to 2005 and a new database of papers published from 2006 to 2015. Using these data, we conducted a meta‐analysis to explore the influence of organismal and environmental characteristics on the magnitude of predator NCEs. Our analysis addressed the following three questions. 1) Does predator–prey coevolution give rise to stronger NCEs than when predator and prey species did not coevolve? 2) What influence does habitat type and refuge availability have on NCEs? 3) How do predator characteristics (cue type, hunting mode and life stage) and prey characteristics (mobility, life stage, specialization, gregariousness and feeding mode) influence NCEs? We found that while NCEs were similar across most measured characteristics, NCEs on prey activity were significantly stronger when predator and prey shared an evolutionary history. Our results support growing evidence that NCEs have a negative effect on prey traits and that behavioral NCEs are stronger than physiological ones. Additional studies are needed to be confident in any emerging patterns, therefore we identify key gaps in the literature on NCEs in arthropod systems and discuss ideas for moving forward.     

2014年全球新药研发报告—— 第一部分：新药和生物药品（Ⅰ）

2014年的新药批准和上市年终报告显示医药行业的活跃性持续保持在高位。截至2014年12月23日,共有55个新药和生物制 品首次上市。此外,29个重要的延伸性新药（新处方、新复方或已上市药物的新适应证）也在2014年首次上市。在这些新上市的药物中, 最多的是抗感染药物,有11个新药和生物制品。它们大多用于多药耐药菌引发的感染或丙肝的治疗。美国再一次成为这些新上市药物最青 睐的市场,该国是2014年半数以上新上市药物的首选地区。不过,日本在2014年开发上市新药的能力显著增强,多年来首次超越欧盟。 另一重要成果是：2014年上市的新药和生物制品中有15个获得罕见病用药资格,5个获得突破性治疗药物资格,还有3个获得合格传染 病产品（QIDP)资格。另外,2014年还有19个产品首度获批,将于2015年年初上市。     

2014年全球新药研发报告——第一部分：新药和生物制品（Ⅲ）

2014的新药批准和上市年终报告显示医药行业的活跃性持续保持在高位。截至2014年12月23日,共有55个新药和生物制品 首次上市。此外,29个重要的延伸性新药（新处方、新复方或已上市药物的新适应证）也在2014年上市。在这些新上市的药物中,最多 的是抗感染药物,有11个新药和生物制品。它们大多用于多药耐药菌引发的感染或丙肝的治疗。美国再一次成为这些新上市药物最青睐的 市场,该国是2014年半数以上新上市药物的首选地区。不过,日本在2014年开发上市新药的能力显著增强,多年来首次超越欧盟。另一 重要成果是：2014年上市的新药和生物制品中有15个获得罕见病用药资格,5个获得突破性治疗药物资格,以及3个获得合格传染病产 品（QIDP)资格。另外,2014年还有19个产品首度获批,将于2015年初上市。     

2014年全球新药研发报告—— 第一部分：新药和生物药品（Ⅱ）

2014的新药批准和上市年终报告显示医药行业的活跃性持续保持在高位。截至2014年12月23日,共有55个新药和生物制品 首次上市。此外,29个重要的延伸性新药（新处方、新复方或已上市药物的新适应证）也在2014年上市。在这些新上市的药物中,最多 的是抗感染药物,有11个新药和生物制品。它们大多用于多药耐药菌引发的感染或丙肝的治疗。美国再一次成为这些新上市药物最青睐的 市场,该国是2014年半数以上新上市药物的首选地区。不过,日本在2014年开发上市新药的能力显著增强,多年来首次超越欧盟。另一 重要成果是：2014年上市的新药和生物制品中有15个获得罕见病用药资格,5个获得突破性治疗药物资格,以及3个获得合格传染病产 品（QIDP)资格。另外,2014年还有19个产品首度获批,将于2015年初上市。     

2012 年全球上市新药

对2012 年全球上市新药的基本信息,包括通用名、商品名、结构式、CAS 号、研发公司、上市国家和主要适应证进行汇总,为新药研发工作者提供参考。     

Preclinical Formulations: Insight,Strategies, and Practical Considerations

A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists.     

Ontogenetic differences of herbivory on woody and herbaceous plants: a meta-analysis demonstrating unique effects of herbivory on the young and the old, the slow and the fast

Defensive modifications in prey traits that reduce predation risk can also have negative effects on prey fitness. Such nonconsumptive effects (NCEs) of predators are common, often quite strong, and can even dominate the net effect of predators. We develop an intuitive graphical model to identify and explore the conditions promoting strong NCEs. The model illustrates two conditions necessary and sufficient for large NCEs: (1) trait change has a large cost, and (2) the benefit of reduced predation outweighs the costs, such as reduced growth rate. A corollary condition is that potential predation in the absence of trait change must be large. In fact, the sum total of the consumptive effects (CEs) and NCEs may be any value bounded by the magnitude of the predation rate in the absence of the trait change. The model further illustrates how, depending on the effect of increased trait change on resulting costs and benefits, any combination of strong and weak NCEs and CEs is possible. The model can also be used to examine how changes in environmental factors (e.g., refuge safety) or variation among predator–prey systems (e.g., different benefits of a prey trait change) affect NCEs. Results indicate that simple rules of thumb may not apply; factors that increase the cost of trait change or that increase the degree to which an animal changes a trait, can actually cause smaller (rather than larger) NCEs. We provide examples of how this graphical model can provide important insights for empirical studies from two natural systems. Implementation of this approach will improve our understanding of how and when NCEs are expected to dominate the total effect of predators. Further, application of the models will likely promote a better linkage between experimental and theoretical studies of NCEs, and foster synthesis across systems.     

The context dependence of non‐consumptive predator effects

Non‐consumptive predator effects (NCEs) are now widely recognised for their capacity to shape ecosystem structure and function. Yet, forecasting the propagation of these predator‐induced trait changes through particular communities remains a challenge. Accordingly, focusing on plasticity in prey anti‐predator behaviours, we conceptualise the multi‐stage process by which predators trigger direct and indirect NCEs, review and distil potential drivers of contingencies into three key categories (properties of the prey, predator and setting), and then provide a general framework for predicting both the nature and strength of direct NCEs. Our review underscores the myriad factors that can generate NCE contingencies while guiding how research might better anticipate and account for them. Moreover, our synthesis highlights the value of mapping both habitat domains and prey‐specific patterns of evasion success (‘evasion landscapes’) as the basis for predicting how direct NCEs are likely to manifest in any particular community. Looking ahead, we highlight two key knowledge gaps that continue to impede a comprehensive understanding of non‐consumptive predator–prey interactions and their ecosystem consequences; namely, insufficient empirical exploration of (1) context‐dependent indirect NCEs and (2) the ways in which direct and indirect NCEs are shaped interactively by multiple drivers of context dependence.     

Application of predator-associated cues to control small brown planthoppers: non-consumptive effects of predators suppress the pest population

Predator non-consumptive effects (NCEs) have been well studied in many ecosystems and NCEs can alter the behavior, morphology and life history of prey, producing strong trait-mediated indirect effects (TMIEs) on host plants. However, studies involving the application of NCEs to control pests in the field, and instances of combined laboratory bioassay and field practice are rare. Here, we examine the development, reproduction and behavior of small brown planthoppers, Laodelphax striatellus (Fallén), when exposed to predator cues from caged predators (Paederus fuscipes Curtis), or predator body extracts (in solvents with different polarities) in the laboratory. Field foliage sprays of these extracts were also used to test their effects on the L. striatellus population and rice plant biomass. Nymph development and egg hatch rate in L. striatellus were not influenced, but adult longevity was shorter, and fecundity and weight gain were lower, when nymphs were exposed to the predator cues. Adults exposed to predator cues also gained less weight and laid fewer eggs. The poorer developmental and reproductive performances might result from lower activity levels observed in threatened L. striatellus. The field foliage sprays of predator cues decreased L. striatellus abundance and increased rice plant biomass, suggesting their possible application for pest control. Predator cues extracted using chloroform increased stronger NCEs and TMIEs, indicating their non-polar characteristics. Our studies advance the understanding of how NCEs shape the life history and behavior of L. striatellus and improve rice growth, laying new foundations for future research on novel pest control materials and methods.

     

Predictive, non-GLP models of secondary pharmacodynamics: putting the best compounds forward

Secondary pharmacodynamic studies of new chemical entities (NCEs) play a critical role in support of efficient drug discovery. In an era in which speed and efficiency are the norm for pharmaceutical discovery, the need to identify NCEs with greater patient tolerability continues to increase. Early use of secondary pharmacodynamic models (in vivo and in vitro) provides the foundation for critical, early decisions regarding lead molecules. Scientifically robust, non-GLP (good laboratory practices) secondary pharmacodynamic studies can eliminate compounds or structural series with undesirable profiles early, and may prove useful in defining structure-activity relationships (SARs) with regards to off-target effects.     

New tools for malaria therapy

In the absence of vaccines, new chemotherapies are needed urgently to help in the prevention and control of malaria. A number of strategies are being followed world-wide in attempts to discover and develop them: (a) resurrecting 'forgotten' molecules; (b) developing new formulations of existing products; (c) finding ways to bypass known toxicological limitations of existing products; (d) looking for combinations of existing products; (e) discovering molecules which reverse the resistance phenotype; (f) identifying 'old' chemical entities (OCEs) for new, antimalarial, indications; (g) discovering new chemical entities (NCEs) directed towards already exploited biological targets; (h) discovering NCEs directed to novel biological targets. Examples of such strategies are given below, together with an indication of their advantages and limitations.     

Fear in the dark? Community‐level effects of non‐lethal predators change with light regime

The total effect of predators on prey is a combination of direct consumption, and non‐consumptive effects (NCEs), such as predator‐induced changes to prey morphology, behaviour and life history. Past research into NCEs has tended to focus on pair‐wise interactions between predators and prey, while in natural ecosystems, species exist in complex communities with several trophic levels made up of multiple autotrophic and heterotropic species. To address how predator NCEs alter the photosynthetic and heterotrophic components of communities, we exposed microbial microcosms to one of three predator treatments: live predators (full predator effect), freeze‐killed predators (NCEs only) or no predators (control), and incubated them under either 12 h:12 h light:dark conditions or continual darkness. Under 12 h:12 h light:dark conditions, NCEs‐only communities never differed from predator‐free communities, but differed from live predator communities. Under conditions of continual darkness, the structure of NCEs‐only communities differed from predator‐free controls, but not from live predator communities, suggesting NCEs can be strong enough to structure communities. Predation threat may cause certain prey to induce defences, such as reductions in movement, which make them less competitive in a community setting. This reduction in competitive ability could lead to these species being driven to extinction through interspecific competition, resulting in similar communities to those in which live predators are present. Heterotrophic species whose rates of resource acquisition depend on movement rates may be affected to a greater extent than autotrophs by predator‐induced reductions in movement, accounting for our observed differences in predator NCEs in ‘dark’ and ‘light’ communities. Our results suggest that the community‐level consequences of fear are greater in the dark. Synthesis Predators affect prey through consumptive and non‐consumptive effects (NCEs) such as alterations to prey behaviour, morphology, and life history. However, predators and prey do not exist in isolated pairs, but in complex communities where they interact with many other species. Using a long term study (>10 predator generations), we show that predator NCEs alone can alter community structure under conditions of darkness, but not in a 12h:12h light:dark cycle. Our results demonstrate for the first time that although the community‐level consequences of predator NCEs may be dramatic, they depend upon the abiotic conditions of the ecosystem.     

Predator biomass determines the magnitude of non-consumptive effects (NCEs) in both laboratory and field environments

Predator body size often indicates predation risk, but its significance in non-consumptive effects (NCEs) and predator risk assessment has been largely understudied. Although studies often recognize that predator body size can cause differing cascading effects, few directly examine prey foraging behavior in response to individual predator sizes or investigate how predator size is discerned. These mechanisms are important since perception of the risk imposed by predators dictates behavioral responses to predators and subsequent NCEs. Here, we evaluate the role of predator body size and biomass on risk assessment and the magnitude of NCEs by investigating mud crab foraging behavior and oyster survival in response to differing biomasses of blue crab predators using both laboratory and field methods. Cues from high predator biomass treatments including large blue crab predators and multiple small blue crab predators decreased mud crab foraging and increased oyster survival, whereas mud crab foraging in response to a single small blue crab did not differ from controls. Mud crabs also increased refuge use in the presence of large and multiple small, but not single small, blue crab predators. Thus, both predator biomass and aggregation patterns may affect the expression of NCEs. Understanding the impact of predator biomass may therefore be necessary to successfully predict the role of NCEs in shaping community dynamics. Further, the results of our laboratory experiments were consistent with observed NCEs in the field, suggesting that data from mesocosm environments can provide insight into field situations where flow and turbulence levels are moderate.     

Consumptive and non-consumptive effects of an invasive marine predator on native coral-reef herbivores

Invasive predators typically have larger effects on native prey populations than native predators, yet the potential roles of their consumptive versus non-consumptive effects (CEs vs. NCEs) in structuring invaded systems remains unclear. Invasive lionfish (Pterois volitans) may have ecosystem-level effects by altering native fish grazing on benthic algae that could otherwise displace corals. Lionfish could reduce grazing by decreasing the abundance of herbivorous fishes (CEs), and/or the predation risk posed by lionfish could alter grazing behavior of fishes (NCEs). To test for these CEs, we manipulated lionfish densities on large reefs in The Bahamas and surveyed fish populations throughout June 2009–2011. In July 2011, NCEs of lionfish were measured by observing fish grazing behavior on algal-covered substrata placed in microhabitats varying in lionfish presence at different spatial scales, and quantifying any resulting algal loss. Lionfish reduced small herbivorous fish density by the end of the 2010 summer recruitment season. Grazing by small and large fishes was reduced on high-lionfish-density reefs, and small fish grazing further decreased when in the immediate presence of lionfish within-reefs. Lionfish had a negative indirect effect on algal loss, with 66–80 % less algae removed from substrata in high-lionfish-density reefs. Parrotfishes were likely driving the response of herbivorous fishes to both CEs and NCEs of lionfish. These results demonstrate the importance of considering NCEs in addition to CEs of invasive predators when assessing the effects of invasions.     

Cytogenetic analysis of mice chronically fed the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine

The cytogenetic effects in mice chronically fed the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) were evaluated by chromosome painting, micronucleated normochromatic erythrocytes (MN NCEs) and sister chromatid exchanges (SCEs). PhIP and numerous other heterocyclic amines have been isolated from cooked foods, and many have been found to be carcinogenic in laboratory rodents. Female C57BL/6N mice were chronically fed a diet containing 0, 100, 250 or 400 ppm of PhIP beginning at 8 weeks of age. Peripheral blood and bone marrow were taken from 5 mice per treatment group at 1, 4 and 6 months from the start of exposure. PhIP was removed from the diet for a final month of the experiment, at which time blood was taken from the remaining animals. Chromosome-specific composite DNA probes for mouse chromosomes 2 and 8 were hybridized to metaphase cells from each tissue. The 1- and 4-month time points showed no statistically significant difference between the control and exposed mice for either tissue in chromosome aberration frequencies. Both MN NCEs and SCEs were analyzed at a single time point during exposure (4 months for MN NCEs and 6 months for SCEs) and again 1 month after removing PhIP from the diet. MN NCEs in the peripheral blood showed a statistically significant dose response, with all values decreasing significantly 1 month after removing PhIP from the diet. SCE frequencies in the peripheral blood showed an approximate doubling compared to control mice, and decreased to control levels 1 month after removing PhIP from the diet. SCE frequencies in the bone marrow of exposed mice showed no difference from the control animals. These results show that chronic ingestion of PhIP by female C57BL/6 mice does not produce persistent cytogenetic damage as visualized by chromosome aberrations, MN NCEs or SCEs.