Scaffold compounds structure-activity relationship

The first class of A3 AR selective antagonists with a bicyclic structure strictly correlated to the adenine nucleus has been claimed in 2005 by Biagi et al. (2005). The authors described the synthesis of a series of N6-ureidosubstituted-2-phenyl-9-benzyl-8-azaadenines whose adenine-like structure was responsible of the antagonist activity and whose phenylcarbamoyl group ensure selectivity at the A3 AR. The structure-activity relationship studies was performed basing on the systematic opt-mization of substituents at the 2-, 6- and 9-positions of the bycyclic scaffold and guided to the desired enhancement of A/Aj selectivity (compound 17, Fig. 7.11). 

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. 

Library design is also influenced by the purpose of the library to be synthesized. For lead generation studies a diverse set of compounds is desired, whereas for lead optimization studies, the library should represent compounds that will provide a representational structure-activity relationship (SAR) for the structural scaffold under investigation. For compounds to be used in HTS, members of the library should be chosen that will provide the maximum information content when evaluated in the screening system. 

The overall process and critical activities for robotic implementation of automated HTS from intake of the researcher s benchtop assay through to the identification of a validated, optimized lead series of compounds around a bona fide chemical scaffold are shown in Fig. 2. The downstream steps of hit confirmation/ validation and structure-activity relationship (SAR) elucidation and hit to lead (HTL) have been included to emphasize that the same robotic assay used for production HTS can and should be used by the HTS team to perform high-volume hit confirmation and first-line automated dose-response analysis of confirmed hits to obtain quantitative potency (IC50) rankings to elucidate the nascent SAR of emergent hit series... 

Systematic structure activity relationships (SARs) around the scaffold of the natural alkaloid yohimbine led to the discovery of 1,2,3,4-tetrahydro-p-carboline (THpC) derivatives that have been shown to be very potent and highly selective 5HT2b receptor antagonists. Of particular interest are 1-substituted-THpC compounds (1 to 4) that were selected for further development (Figure 6.1). 

Rational inhibitor design offers a compelling alternative for the identification of protein-protein disrupters as it is based on a structural knowledge of the interface. In particular, synthetic scaffolds that mimic the key elements of a protein surface can potentially lead to small molecules with the full activity of a protein domain, a fraction of the molecular weight, and no peptide bonds. Furthermore, lead compounds derived from rational design can be readily optimized by structure-activity relationship (SAR) studies. 

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