Compounds, early identification

The potential of drugs to cause QT prolongation and the associated risk of cardio-toxicity remains an important issue in drug development. Although the advent of automated electrophysiological systems and other predinical screens has helped in early identification of hERG channel blockers, the outcome can be highly unsatisfactory. The process is wasteful and expensive and the development of potentially valuable compounds is halted. The wealth of information continually uncovered... 

Considerable effort has been expended in recent years on the odorous compounds formed in autoxidized dairy products. Although some of the early identification studies lack present-day sophisticated methodology, may be incomplete, and do not differentiate between their isomeric forms of the various compounds, their contribution to the knowledge of the products of autoxidation in dairy products is invaluable. 

Early identifications of long-chain monocar-boxylic acids (fatty acids) are generally believed to have been terrestrial contaminants (e.g., Smith and Kaplan, 1970). However, short-chain mono-carboxylic acids (extractable compounds in Murchison (Figure 1 and Table 1 Yuen and Kvenvolden, 1973 Lawless and Yuen, 1979 Yuen et al., 1984). They show complete structural diversity with all C2-C5 isomers present and with equal concentrations of both branched- and straight-chain isomers there is a general decrease in the abundance of short-chain monocarboxylic acids with increasing carbon number. 

In silico tools make a significant contribution to the SAR-based early identification of potential toxicity. An increasing volume of published preclinical and clinical toxicity data are collected and used to build structure-related searchable databases. These expert knowledge databases can analyze chemical structures and match them with potential mechanisms of toxicity. DEREK for Windows (Lhasa Ltd.)39 is one of such broadly used knowledge-based expert systems to provide toxicology alerts for new compounds. Although certainly not comprehensive, numerous efforts have been made to predict hepatotoxicity. Recently,... 

Another major benefit to medicinal chemists of providing pH profile data is the early identification of stability issues - if the solubility and calibration spectra do not match, it will indicate that degradation of the compound may be occurring. 

One property of a crystalline compound is its ability to form polymorphs, that is, more than one crystal form for the same molecular entity. The phenomenon of polymorphism plays a critical role in the pharmaceutical industry because it affects every phase of drug development, from initial drug discovery to final clinical evaluation, including patent protection and competition in the market. A critical challenge is the early identification of possible polymorphs. Chapters 2 and 3 will address this key issue. 

The effects of a rather distinct deformed shell at = 152 were clearly seen as early as 1954 in the alpha-decay energies of isotopes of californium, einsteinium, and fermium. In fact, a number of authors have suggested that the entire transuranium region is stabilized by shell effects with an influence that increases markedly with atomic number. Thus the effects of shell substmcture lead to an increase in spontaneous fission half-Hves of up to about 15 orders of magnitude for the heavy transuranium elements, the heaviest of which would otherwise have half-Hves of the order of those for a compound nucleus (lO " s or less) and not of milliseconds or longer, as found experimentally. This gives hope for the synthesis and identification of several elements beyond the present heaviest (element 109) and suggest that the peninsula of nuclei with measurable half-Hves may extend up to the island of stabiHty at Z = 114 andA = 184. 

As early as 1967, IFF chemists (11), in an in-depth study of jasmin absolute, identified an ultratrace amount of one of the key compounds in the entire fragrance repoitoire, hydroxycitroneUal [107-75-7] (21). This chemical has been used for many years in almost every "white flower" fragrance to give a very diffusive and lasting lily-of-the-valley and jasmin note, but this represents the only known identification of the compound in nature. This illustrates that the human nose can often predict the presence of a molecule well before the instmmentation becomes sufficiently sensitive to detect it. 

The oldest effective drug for the treatment of this disease is indisputably quinine. Although the antipyretic activity of cinchona bark was known to the Incas, it remained for the Jesuit missionaries to uncover its antimalarial properties in the early seventeenth century. The advance of organic chemistry led to the isolation and identification of the alkaloid, quinine, as the active compound at the turn of this century. The emerging clinical importance of this drug led up to the establishment of cinchona plantations in the Dutch East Indies. This very circum-... 

In as far as other analytical methods are concerned, many specific reactions have been elaborated for the quantitative determination of 2-deoxy aldoses. 2-Deoxy-D-ribose (2-deoxy-D-erythro-pentose), a compound which was recognized early as playing an important role in biological systems, has been of particular interest. Overend and Stacey (43) have given a critical review of the methods available until 1952 for the estimation of 2-deoxy pentoses. A recent summary of specific methods for the identification and quantitative estimation of the different classes of deoxy sugars has been prepared by Dische (13). 

Attempts to obtain fluoride compounds of niobium and tantalum with alkali earth and some transitional metals were made as early as one hundred years ago, but synthesis and identification methods were described only at later times. 

Manley-Harris and Richards (Missoula, Montana) have compiled a comprehensive account of the dianhydrides of D-fructose and related compounds, more than 30 in all. These compounds, several of which are of importance in the sugar industry, have in the past presented significant problems in their chemical characterization. Their chemistry was surveyed as early as 1945 by McDonald in Volume 2 of this series, and discussed again in Volume 22 by Verstraeten. The current article furnishes detailed NMR data for each of the anhydrides, providing definitive reference data for accurate identification and correlation with earlier literature, where erroneous structural attributions are rather frequent. 

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