New chemical entities NCEs

Structural information chemical formula and stereochemistry in the case of a New Chemical Entity (NCE) or amino acid sequence and glycosylation sites in the case of a biotech product... 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products. 

It is important to understand the need for the multiple assays that are now routinely performed by most pharmaceutical companies to measure various absorption distribution metabolism and excretion (ADME) parameters to determine the pharmacokinetic (PK) properties of new chemical entities (NCEs). The goal of new drug discovery is to find NCEs that have the appropriate... 

Approximately 10% of new chemical entities (NCEs) show serious adverse drug reactions (ADRs) after market launch. Such events usually result in new black box warnings by the US Food and Drug Administration (FDA), label change or market withdrawal. The most common causes for these actions are hepatic toxicity, hematologic toxicity and cardiovascular toxicity [2], Reasons for such ADRs, which are identified only after NCEs are launched on the market, include the narrow spectrum of clinical disorders and participating patient profiles in clinical studies as well as the fact that serious ADRs are often rare and that the number of patient exposures required to identify such occurrences sometimes may range over a few millions [3],... 

Drag development is a time-consuming and costly process. Recently, the need of very sensitive and selective assays for the complete characterization of New Chemical Entities (NCE) has become very stringent. 

Since the origin, the most efficient source of drugs and biological active molecules is Nature. As reported by Newman and Cragg in a recent review [1], at least 25-30% of New Chemical Entities (NCE) going under study for pharmaceutical and clinical applications are primarily derived from Nature (N) or Natural Derived (ND), while only 30% are merely synthetic, as reported in Figure 2. 

Lead optimization of new chemical entities (NCEs) based on pharmacokinetic behavior plays a major role in modern drug discovery. Despite advancement of drug delivery methods, the oral route remains the most frequent route of administration for approved new drugs. Therefore, during lead optimization it is essential to identify NCEs with sufficient oral absorption predicted using a variety of in vitro and in vivo assays. It is well recognized that in order for a NCE to achieve reasonable oral absorption, it will need to have adequate aqueous solubility, as well as intestinal permeability [1], Recent advancements in chemistry, such as parallel and combinatorial synthesis, have resulted in a multifold increase in the number of compounds that are available for evaluation in new drug discovery. Furthermore, a variety of improved structural chemistry... 

For the accumulated costs and resources devoted to the development of a new chemical entity (NCE) or new molecular entity (NME) to make sense financially, the commercial potential of the compound must be evaluated in a rigorous manner. Compounds whose expected financial performance does not warrant these high investment costs must be abandoned or out-licensed as soon as possible so as to direct resources toward more profitable endeavors. By operating effectively, a well-designed drug discovery and development process can focus its efforts to operate efficiently on the compounds that will maximize cash flow to the pharmaceutical firm. 

During early phase development there is limited knowledge about the chemistry of the new chemical entity (NCE) with respect to synthetic impurities and degradation pathways and kinetics. It is, therefore, desirable to develop an array of methods that show applicability to a broad range of potential impurities, degradation products, and excipients. The methods are intended to provide the information necessary to guide the improvement of a synthesis route or a new drug formulation. 

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