Structure-activity relationships development

The generally accepted structure-activity relationships developed in the early work in the quinolone series held that the N-1 substituent needed to be small and aliphatic. This picture was upset in a dramatic way with the discovery of the excellent potency and antimicrobial spectrum of difloxacin (45) and its congeners in which the substituent on N-1 is an aromatic ring. The synthe-... 

Abstract Inhibitors of the kinases controlling the cell cycle have emerged as an important therapeutic modality for the treatment of cancer. Drug discovery efforts have focused on inhibitors of the cyclin-dependent kinases, the Aurora kinases, and Polo-like kinases. Agents for each kinase are now advancing in human clinical trials. In this review we will summarize the work in this area with special emphasis on the structural biology and structure-activity relationships developed for the many chemotypes explored. 

Thus, structure-activity relationships developed to estimate levels in biological media based on the partitioning properties of a chemical may not provide accurate information for isophorone. Furthermore, only one bioaccumulation study was available. In this study, which indicated a low potential for bioaccumulation, fish were exposed to isophorone in water rather than in food. From these data, it appears that food chain bioaccumulation may be occurring, and a clearer understanding of the potential for this would aid in determining how levels in the environment affect the food chain and potentially impact on human exposure levels. 

More detailed studies of epimerization in the azepanone series indicated that these compounds were configurationally stable over a pharmaceutically relevant time-scale [19]. Structure-activity relationships developed in previous series were applied successfully to the azepanone scaffold, yielding extremely potent enzyme inhibitors that exhibited good diastereomeric selectivity as well as reasonable selectivity versus cathepsin K homologues. 

Other pharmacological activities have also been correlated with quantum-chemically derived descriptors. For instance, the quantitative structure-activity relationship developed for the antibacterial activity of a series of monocyclic (i-lactam antibiotics included the atomic charges, the bond orders, the dipole moment, and the first excitation energy of the compound [103]. The fungicidal activity of A3-l,2,4-thiadiazolines has been correlated with an index of frontier orbital electron density derived from semi-empirical PM3 molecular orbital calculations [104],... 

Until recently only few examples of 5-substituted quinolones were reported and no systematic structure-activity relationships developed. In 1988 and 1989 two publications have reported the synthesis of 5-nitro- and 5-amino-, 8-fluoro- and 5,8-difluoroquinolones [34, 35, 100]. 5,8-Difluoro derivatives have been easily prepared from 2,3,4,5,6-pentafluorobenzoic acid following the same methodology used for mono-8-fluoro derivatives (Fig. 12). 5-nitro and 5-amino analogs have been obtained starting from 2,3,4,5-tetrafluorobenzoic add as shown in Fig. 26. 

The structure activity relationship developed for these dihydropyridines showed that optimal activity was derived from BTF, using anilines containing a halogen, cyano or CFj group in the para position and small aliphatic and cyclic ketones and acetophenones. 

The reaction of NO3 with methyl n-butyl ether has not been studied. On the basis of structure-activity relationships developed later in this chapter (section III-H), a rate coefficient of fe 2.5 x 10" cm molecule" s" is estimated at 298 K. 

There are no data available for this reaction. However, on the basis of structure-activity relationships developed in section III-H, an estimate of A = 5 x 10... 

The reliability of the in silico models will be improved and their scope for predictions will be broader as soon as more reliable experimental data are available. However, there is the paradox of predictivity versus diversity. The greater the chemical diversity in a data set, the more difficult is the establishment of a predictive structure-activity relationship. Otherwise, a model developed based on compounds representing only a small subspace of the chemical space has no predictivity for compounds beyond its boundaries. 

BT Luke. Evolutionary programming applied to the development of quantitative structure-activity relationships and quantitative structure-property relationships. J Chem Inf Comput Sci 34(6) I279-1287, 1994. 

On the other hand, multimodality of biological activities of melatonin is well known. Therefore various derivatives are needed for carrying out its structure-activity relationship study. 1-Hydoxymelatonin (19) would be a suitable seed for developing yet unknown results. 

Among others, 11 was included in a series of drugs to study quantitative structure-activity relationships (96KFZ(6)29, 98MI7, 99BMC2437). A statistically significant CoMFA model was developed for describing the... 

Bis(oxazohnes) figands have been so widely used for the Diels-Alder reaction between N-2-alkenoyl-l,3-oxazolidine-2-one and cyclopentadiene that Lipkowitz and Pradhan developed a QSAR (quantitative structure-activity relationship) using Comparative Molecular Field Analysis (CoMFA) for a set of 23 copper-catalysts containing mainly bis(oxazoline) figands. The generated... 

Traditionally, in pursuit of their structure-activity relationships, medicinal chemists had focused almost exclusively on finding compounds with greater and greater potency. However, these SARs often ended up with compounds that were unsuitable for development as pharmaceutical products. These compounds would be too insoluble in water, or were not orally bioavailable, or were eliminated too quickly or too slowly from mammalian bodies. Pharmacologists and pharmaceutical development scientists for years had tried to preach the need for medicinal chemists to also think about other factors that determined whether a compound could be a medicine. Table 1.1 lists a number of factors that determine whether a potent compound has what it takes to become a drug. Experimentally, it was difficult to quantitate these other factors. Often, the necessary manpower resources would not be allocated to a compound until it had already been selected for project team status. 

With the development of accurate computational methods for generating 3D conformations of chemical structures, QSAR approaches that employ 3D descriptors have been developed to address the problems of 2D QSAR techniques, that is, their inability to distinguish stereoisomers. Examples of 3D QSAR include molecular shape analysis (MSA) [26], distance geometry,and Voronoi techniques [27]. The MSA method utilizes shape descriptors and MLR analysis, whereas the other two approaches apply atomic refractivity as structural descriptor and the solution of mathematical inequalities to obtain the quantitative relationships. These methods have been applied to study structure-activity relationships of many data sets by Hopfinger and Crippen, respectively. Perhaps the most popular example of the 3D QSAR is the com-... 

Walker ID, Jaworska J, Comber MHI, Schultz TW, Dearden JC. Guidelines for developing and using quantitative structure-activity relationships. Environ Toxicol Chem 2003 22 1653-65. 

Woo Y-T, Lai DY, Argus ME, Arcos JC. Development of structure-activity relationship rules for predicting carcinogenic potential of chemicals. Toxicol Lett 1995 79 219-28. 

Due to their demanding synthesis, diamondoids are helpful models to study structure-activity relationships in carbocations and radicals, to develop empirical computational methods for hydrocarbons, and to investigate orientational disorders in molecular crystals as well [5,32]. 

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