Biphenyl tetrazole

In the published example, 502 compounds from the MDL Drug Data Report (MDDR) (26) that were active against a GPCR target and also contained a biphenyl tetrazole moiety were used to generated a privileged four-point 3D... 

JH Toney, PM Fitzgerald, N Grover-Sharma, SH Olson, WJ May, JG Sundelof, DE Vanderwall, KA Cleary, SK Grant, JK Wu, JW Kozarich, DL Pompliano, GG Hammond. Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo-beta-lactamase. Chem Biol 5 185-196, 1998. 

G. G. Hammond, Chem. Biol, 5, 185 (1998). Antibiotic Sensitization Using Biphenyl Tetrazoles as Potent Inhibitors of Bacteroides fragilis Metallo-P-lactamase. 

When used for relative similarity and diversity, only potential pharmacophores that contain the defined special centre-type are used. The frame of reference for similarity/diversity studies is thus changed to one that is focused on the feature of interest distances are now measured relative to this special centre. For example, the special centre could be the centroid of a substructure [10] such as biphenyl tetrazole or diphenylmethane, enabling the calculation and comparison of all 3D pharmacophoric shapes that contain this substructure the substructure is said to be privileged . For structure-based design, the potential pharmacophores in a site can be restricted to those that contain a specific site point (e.g. in a pocket, or at the entrance to a pocket). In the context of combinatorial library design, the relative measure can be those pharmacophoric shapes that contain a special site-point that represents where the attachment point for a reagent would be. In figure 1, the special point would be centre-type number 3, which can be reserved for this purpose. 

D. E. Vanderwall, K. A. Cleary, S. K. Grant, J. K. Wu, J. W. Kozarich, D. L. Pompliano, and G. G. Hammond, Chem. Biol., 5, 185 (1998). Antibiotic Sensltatlon Using Biphenyl Tetrazoles as Potent Inhibitors of Bacteroides fragilis Metallo-P-Lactamase. 

Figure 5.19. Example of a "privileged" four-point pharmacophore. Here biphenyl tetrazole, a substructure seen in a number of GPCR inhibitors, is specifically defined as a pharmacophore feature, using a centroid dummy atom. Only pharmacophores that include this type are included in the fingerprint, thus providing a relative measure of diversity/similarity with respect to the privileged feature.

Figure 5.22. Example of pharmacophore feature assignments involving the biphenyl tetrazole "privileged" substructure and the total four-point potential pharmacophores calculated for a GPCR antagonist. Note that just the subset (40%) of the total pharmacophores that contained the "privileged" substructure was used for the library design.

A variant of the THP linker, in which the TH P unit is attached via an ester function to fhe sohd support, has been applied to the synfhesis of biphenyl tetrazole derivatives 47, as outlined in Scheme 23 [51]. Bromophenyl tetrazole was attached to polymer-bound dihydropyran to yield 46. This step was followed by Suzuki coupling and acid-catalyzed release from the support to yield fhe desired compounds 47. 

Scheme 2.9 Example of the synthesis process for the production of the biphenyl tetrazole group...

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