Discovery phase, candidate

In the discovery phase, a reaction route is developed to allow synthesis of a maximum number of analogues for pharmacological testing. Since the focus is on synthetic flexibility, issues of scale are not central. Once a lead compound exhibits a useful pharmacological activity and is identified as a candidate for further development, larger scale synthesis is required to evaluate stability, bioavailability, toxicity, physicochemical properties, and other compound properties. The Chemical Development Department is usually involved in the preparation of supplies for these activities. 

The productivity of pharmaceutical R D in proportion to spend has fallen substantially to the point that its very existence is under threat [1,2]. It has been estimated that 93-96% of nominated candidate drugs fail at some stage in development [3] all attrition, from the start of compound optimization in the discovery phase of a project to launch on the market, is probably closer to 99%. Therefore, there is an urgent imperative to directly address the reasons for attrition, which from candidate drug nomination onwards can be divided into three broad categories [3-5] ... 

The paradigm shift from critical activities from later drug development to earlier discovery phases some years ago has effectively led to a change in lead optimization and added a new dimension of complexity, while it is envisioned that from a multidimensional, data-driven process more suitable candidates in accord with the therapeutic target product profiles may emerge for the treatment of currently unmet medical needs. 

To date, the frame in the discovery phase, within the global biomarker finding process, is the common aspect of all metabolomic works linked to AD. Thus, most of metabolomic studies have been focused in the search of new biomarker candidates in the apparition and development of AD with high impact on novel hypotheses generation. Currently, there is a growing need to reliably validate those findings by increasing the cohort of clinical patients, to measure and validate the potential of the revealed biomarkers. 

Mechanically encoded libraries are best suited to synthesis of individual compounds rather than mixtures. The amount of each compound produced can be small or large and is limited only by the size of the packets and related physical limitations. Since reactions can be carried out in conventional glassware, mechanically encoded libraries offer an inexpensive entry into large-library synthesis. The method is applicable throughout most of the dmg discovery process with the possible exception of the very earliest discovery phase and the very latest candidate selection phase. 

During the discovery phase, when availability of compound is at a premium, the formulation of a simple injectable product for use in animal studies can be problematical. If a drug candidate required for formulation as a parenteral product is non-ionizable, lipophihc or does not form a water-soluble salt with acceptable properties, solubilization by use of cosolvents should be considered as the next option. In cases... 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

Tiller et al. [289] reported the use of accurate LC-MS/MS data from a Q-TOF system as a first-line approach for metabolite identification studies in the discovery phase of the drug development. In this approach, first, the MS/MS spectrum of the parent compound under conditions of high mass resolution is obtained in order to support the proposed fragmentation pattern by elemental composition data. In the next step of the accurate mass approach to metabolite identification, the in vitro samples of drug candidates from incubations in liver microsomal preparations or hepatocytes are analyzed by LC-MSE on the Q-TOF mass spectrometer. Data are... 

Safety lead optimization efforts are used to maximize resources and early decision-making for the purposes of reducing costs and animal use and removing the least favorable compounds early during the discovery phase, when there is most flexibility in optimizing the candidate molecule. The ultimate goal is to identify a lead development candidate that has the most superior safety characteristics and, for those safety issues identified, a well-characterized risk assessment to reduce clinical attrition due to toxicity and inform the clinical development plan. 

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