Discovery support

The incorporation of 14C into compounds at a suitable site often requires extensive and complicated syntheses, and thus a relatively long time. This usually means that 14C-labeled compounds are unsuitable for studies to be carried out during discovery. There are however, very rapid methods for incorporating 3 H into compounds. The newer methods, generally involving metal-catalyzed exchange reactions [15-18], in our experience, mean that suitable labels can often be prepared in 2 or 3 weeks. These time scales make the approach viable for discovery support. Additionally, and importantly, these methods can lead to specific incorporation of tritium. 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

ChemOvation Ltd., founded in 1998, focuses on providing an integrated drug discovery support service via collaborative programs, and the manufacture of innovative compound libraries. Apart from that, their range of services includes chemistry development, automated parallel synthesis, scale-up, process development, and screening. 

Tong, W.Q. and Whitesell, G. (1998l)n situ salt screening useful technique for discovery support and preformulation studie harm. Dev. Tech., 3, 215-223. 

Formulation Strategies and Practice Used for Drug Candidates with Water-Insoluble Properties for Toxicology, Biology, and Pharmacology Studies in Discovery Support... 

Details the drug discovery support area for designing new drug candidates with improved aqueous solubility and maximized exposure... 

Gordon, M.D. and Lindsay, R.K. 1996. Toward discovery support systems A replication, reexamination, and extension of Swanson s work on literature-based discovery of a connection between Raynaud s disease and fish-oil. Journal of the American Society for Information Science, 47(2) 116-128. 

Several analogues of the dolastatins, potent cytotoxic compounds originally derived from the Indian Ocean seahare, Dolabella auricularia, have now been found in the marine cyanobacteria, Lyngbya majuscula and Symploca hydnoides. These discoveries support the proposal that the dolastatins isolated from D. auricularia are of dietary origin. The implications of such an observation to natural products programmes is discussed. Aspects of the structure elucidation of these complex molecules are also presented. 

As for any bioanalytical method, the extent of validation for an immunoassay should be related to the intended application of the assay. Thus, if an immunoassay is intended to support rapid screening in discovery R D, the characterization of specificity and the accuracy and precision specifications may be less stringent than if the assay is used to support pre-clinical and clinical development studies. Indeed, an assay for discovery support may be designed to detect active metabolites as well as parent molecule, so that... 

This approach provides minimal sample cleanup with little or no method development effort. The solid-phase extraction desalts and depro-teinizes the samples method selectivity is furnished by the LC/MS/MS system. The approach is capable of high throughput (up to 400 samples/hr) and appears to work a large percentage of the time, making it well suited for drug discovery support. 

Tong, W. Q., Whitesell, G. In situ salt screening — a useful technique for discovery support and preformulation studies. Pharm. Dev. Technol 1998, 3(2), 215-232. 

TABLE 15.1 Examples of Application of Pharmaceutical Properties for Discovery Support... 

Although many individual choices for sample preparation exist, sometimes the combination of two techniques yields a more desirable result. Within a drug discovery environment, however, throughput and cost are important factors that influence the choice of sample-preparation methods. The protein-precipitation procedure can quickly yield a sample that is ready for analysis, but its potential for carryover of matrix interferences is problematic. The isolated supernatant can be filtered or centrifuged before injection, but these procedures remove only particulates or proteinaceous material, not the materials that cause matrix interferences. Thus, protein precipitation is sometimes followed by LLE, SPE, or an on-line technique for a more selective cleanup before analysis. A particularly challenging sample-preparation requirement is the analysis of animal tissues, as is commonly performed in drug-discovery support laboratories that perform drug uptake studies. Here, a series of sequential sample-preparation steps are common [121]. 

Traditional, and perhaps, manual approaches for method development would be too time-consuming to perform within a drug discovery environment. As a result, automated method development routines, such as the procedure to generate optimized SRM tables for PK screening, are an essential requirement for drug discovery support [60],... 

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