Continuous SARs

A set of inhibitors of the coagulation factor Xa is found to present prototypic continuous SARs. There is detectable correlation between 2D and 3D molecular similarity and most similar 2D structures bind very similarly and with... 

A different example is provided by a set of elastase inhibitors. These ligands are also related by continuous SARs. This is reflected by the presence of highly potent inhibitors with diverse structures and, in addition, structurally similar ligands that display only minor potency differences. However, in contrast to factor Xa, 3D analysis reveals a more complex picture. Specifically, elastase accepts multiple binding modes, each of which is adopted by structurally... 

Continuous SARs. The set of factor Xa inhibitors discussed above presents a prime example of continuous SARs. As illustrated in Figure 4.7(a), many compounds show a high degree of structural diversity but have rather similar potency values and, in addition, similar compounds also have similar potency. These characteristics are reflected by a high SARI score of 0.80 produced by high continuity and low discontinuity scores, which is indicative of a continuous SAR. The continuity score of 0.71 reflects high intra-class structural diversity, whereas the discontinuity score of 0.12 indicates that similar ligands... 

Figure 4.9 Carbonic anhydrase inhibitors following a continuous SAR. Within a set of sulfonamides, increasing structural diversity is accompanied by gradual changes in potency. 2D similarity is reported on the basis of MACCS Tc values for pair-wise comparisons using the molecule on the left-hand side as the reference structure.

One should also consider that the potential success of similarity methods is not exclusively determined by representation- and reference frame-dependent SAR characteristics. Importantly, the success of similarity methods is also influenced by more technical factors. In other words, SAR categories principally determine if similarity search calculations can succeed whether they actually do is another question. For example, the intrinsic structural diversity of active compounds related by many continuous SARs makes similarity calculations particularly difficult because remote similarity relationships must be... 

Figure 4.10 Example of a heterogeneous SAR. Four inhibitors of vascular endothelial growth factor receptor (YEGFR-2) tyrosine kinase are shown. The two inhibitors at the top have different core structures but equally high potency and are thus part of a continuous SAR. By contrast, closely related analogs of each inhibitor shown at the bottom have several orders of magnitude lower potency, which is a characteristic feature of discontinuous SARs.

Figure 11.2 Heterogeneous SAR combining continuous and discontinuous SAR. Four cathepsin S inhibitors dispiay different SAR behavior, inhibitors reiated by a continuous SAR have comparabie potency vaiues despite structurai variations (top). In the...

Continuing SAR studies in the dlbenzo[b,f]thlepln and related 6,7,6 systems have shown that substitution by chlorine in the 9-posltlon of perathiepln (2a) results in diminished activity. All eight possible aryl-monochloro Isomers of perathiepln have now been synthesized, and of... 

The most connnon detectors used for TOF-SARS are continuous dynode channel electron multipliers which... 

A lead is variously defined in the pharmaceutical industry as a compound derived from a hit with some degree of in vitro optimization (potency in primary assay, activity in functional and/or cellular assay), optimization of physical properties (solubility, permeability), and optimization of in vitro ADME properties (microsomal stability, CYP inhibition). Moreover, a lead must have established SAR/SPR around these parameters such that continued optimization appears possible. A lead may also have preliminary PK and in vivo animal model data. However, it is the task of the lead optimization chemist to improve PK and in vivo activity to the levels needed for identification of a clinical candidate. 

D. S. Garmatyuk and R. M. Narayanan, Ultra wide-band continuous-wave random noise arc-SAR , in IEEE Transactions on Geoscience and Remote Sensing, Volume 40, Issue 12, Dec. 2002, pp. 2543-2552. 

While not exactly the same as the methods described above in that DOE cannot be applied retrospectively to diverse datasets, it has been used very successfully to guide the selection and evaluation of compounds from combinatorial libraries (59,60). However, DOE has been successfully applied only in cases where limited libraries of related compounds (e.g., peptides) were being evaluated. The reason for this is intuitively obvious, as one of the assumptions of DOE is that variability in the descriptors is continuous and related to activity over a smooth response surface, so that trends and patterns can be readily identified. With HTS data both of these assumptions are generally not true, as molecules can display discontinuous responses to changing features, and the SAR of even related compounds does not map to a smooth continuous response surface (for example, Fig. 2). 

Major advancements in the chemistry of pyrazoles, imidazoles, triazoles, tetrazoles, and related fused heterocyclic derivatives appeared in 1999. Solid-phase combinatorial chemistry of benzimidazoles and tiiazoles has been particularly active. Synthetic routes to all areas continue to be pursued vigorously with improvements and applications. In medicinal chemistry, synthesis and structure-activity relationship (SAR) studies utilizing these core structures have been exploited heavily. The physical organic chemistry of pyrazoles and imidazoles continue. 

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