Privileged structure

A closer inspection of the chemical structures of these compounds shows that they contain a modification of the diphenylmethane moiety, a diphenylamine. 

This is indeed the case. In addition to gamma-aminobutyric acid (GABA), opiate and cholecystokinin receptor activities, the benzodiazepine scaffold is also found in muscle relaxants, antidepressants, neuroleptics, hypnotics, NK-1 receptor and vasopressin receptor antagonists, integrin antagonists, farnesyl transferase and phosphodiesterase inhibitors, potassium channel modulators, and others. 

Some more examples of privileged structures include phenethylamines, steroids, arylpiperazines, arylspiropiperidines, and biphenyltetrazoles (Fig. 3.6) [7,26]. 

Certain areas of molecular space, such as regions containing privileged structures, are rich in hits. The inverse argument—molecular space regions without privileged structures 

FIGURE 9.19 Walking a molecule from hit space to drug space by six sequential structural changes 

Sir James Black once said that The most fruitful basis for the discovery of a new drug is to start with an old drug [73]. In analogy to this, it could be considered a promising approach to base new compound libraries on known biologically active substructures. 

It has also been found that there are privileged structures like benzimidazoles, spiropiperidines, or dihydropyridines, which show activity toward several target classes [76]. Analyses like this can be used to design compound libraries with a higher probability for success. However, it is questionable if there are many such structural features with selectivity for a certain target class [77], which is why this concept is certainly usefiil for building general compoimd collections, but maybe not selective ones. 

There are a number of drugs with a macrocyclic structure [89]. Interestingly, many of them do not obey Lipinski s rule of fie [90]. Also, a chemoinformatic analysis of bioactive macrocycles [91] shows that different subtypes such as peptides, isoprenoids, and polyketides have different distributions of ring sizes. The greatest synthetic challenge is the ring closing step, for which there are a number 

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There is evidence to suggest that drug-like structures exist in clusters in chemical space (privileged structures). Identification of these can greatly enhance success in screening. 

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

Indoles are designated as privileged structures in medicinal chemistry because they are important constituents of bioactive natural products and... 

Patchett AA, Nargund RP. Privileged structures—an npdate. Anna Rep Med Chem 2000 35 289-98. 

Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP. Recognition of privileged structures by G-protein coupled receptors. J Med Chem 2004 47 888-99. 

The discovery of the bisphospholane scaffold as a new privileged structure for asymmetric induction in alkene hydroformylation has triggered research for new and improved bisphospholane-type ligands. In this context (k,k)-Ph-bpc has been identified as an excellent ligand for asymmetric hydroformylation, which gives state-of-the-art regio- and enantioselectivities... 

By focusing the entire compound collection on the pTyr-pyridone scaffold, the researcher made use of a privileged structural element, since the pyridone was repeatedly utilized to induce /3 strand conformations in serine and cysteine protease inhibitors [157,158]. From this point of view, the potential of a modu-... 

Fisher, M. J., Backer, R. T., Collado, L, et al. (2005) Privileged structure based ligands for melanocortin receptors—substituted benzylic piperazine derivatives. Bioorg. Med. Chem. Lett. 15, 4973-4978. 

Guo, T. and Hobbs, D.W. Privileged structure-based combinatorial libraries targeting G protein-coupled receptors. Assay Drug Dev. Tech. 2003, 1, 579-592. 

Rational Selection of Building Blocks Based on Privileged Structural Motifs... 

Privileged Structures and Substructures in the Design of Pharmacologically Relevant Combinatorial Libraries... 

Analysis of Privileged Structural Motifs Structure Dissection Rules... 

To correctly address the problem of identification of target-specific privileged motifs, one should take into account the phenomenon of bioisosterism [26]. Thus, several different bioisosteric structures can constitute only one distinct privileged structural motif. In order to include all possible bioisosteric analogs into one cluster, we use a special algorithm of ChemoSoft based on a collection of rules for bioisosteric conversions described in literature. AH bioisosteric analogs are considered similar with similarity coefficient 1 if they have identical substituents around the central bioisosterically transformed fragment. 

I 72 CPCR-specific Combinational Libraries Based on the Concept of Privileged Substructures Tab. 12.4 Some privileged structural motifs of Dopamine D2 agonists... 

Horton, D.A., Bourne, G.T., and Smythe, M.L. The combinatorial synthesis of bicydic privileged structures or privileged substructures. Chem. Rev. 2003, 303, 893-930. 

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