Biosterism

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

Biosterism-based approach in drug design 96CRV3147. 

Schuffenhauer A, Gillet VJ, Willett P. Similarity searching in files of 3D chemical structures analysis of the BIOSTER database using 2D fingerprints and molecular field descriptors. J Chem Inf Comput Sci 2000 40 295-307. 

In addition to triazole-based biosteres of (382), thiazoles and imidazoles have also been investigated by Lange et al. [311]. The three series of compounds were assessed on their CBi binding affinity and functional activity... 

Turin,University European Vinyls Corp. Bioster SpA... 

BioSter— pairs of biologically similar structures for bioisosterism applications... 

Chem. Inf. Comput. Sci., 43, 391-405. Schuffenhauer, A., Gillet, V.J. and Willett, P. (2000) Similarity searching in flies of three-dimensional chemical structures analysis of the BIOSTER database using two-dimensional flngerprints and molecular fleld descriptors. /. Chem. Inf. Comput. Sci., 40, 295-307. 

Useful reviews on redox transformations of thiophen derivatives (179 references), on the stereochemistry of carbonyl derivatives of five-membered heterocycles (257 references), on synthetic approaches to dihydrothiophens (135 references), and on biosteric thiophens" have been published. Aspects of thiophen chemistry have been treated in reviews on the synthesis of heterocycles by thermal [2 + 2] cycloaddition reactions of acetylenes and on aspects and perspectives of organic heterocyclic chemistry. A review comparing the chemistry of thieno[2,3-h]- and thieno [3,2-i ]-thiophen with that of benzo[ft] thiophen and quinoline has been published. In Advances in Heterocyclic Chemistry, the development of benzo[6] thiophen from 1968 to 1980 and of selenophen from 1970 to 1980 was presented. Other aspects of thiophen chemistry are treated in chapters on Dewar Heterocycles," on Cyclizations under Vilsmeier Conditions, on Polyfluoroheteroaromatic Compounds, and on Reactions of Benzyne with Heterocyclic Compounds. " Several dissertations treating various aspects of thiophen chemistry have appeared. " ... 

The retrieval of all 3D structures from a database considered to be similar to a given target structure is comparable with 2D similarity searching. 3D similarity searching raises the problem of conformational flexibility. Schuffenhauer et analysed the BIOSTER database by similarity search using 2D fingerprints and molecular field descriptors. A comprehensive overview on pharmacophore perception and 3D database searches is given in references 101 and 102. 

Azaindoles, also knoAvn as pyrrolopyridines, are biosteres for indole. Depending on the position of the nitrogen atom, they are named 4-azaindole, 5-azaindole, 6-azaindole, and 7-azaindole, respectively, as shown below. 

As biosteres of benzene, thiophene and benzothiophene have enjoyed much success in drug discovery. In fact, pharmaceuticals containing thiophene or benzothiophene moieties accounted for several billion dollars a year in sales through much of the 2000 s. Syntheses of many of these therapeutics are well known and provide excellent case studies in the chemistry of thiophenes and benzothiophenes and their utility. 

Indazoles have been used as the biosteres of indoles in drug discovery. In the synthesis of the nonsteroidal anti-inflammatory drug (NSAID) bendazac, benzylaniline was used as its starting material. Nitrosolation was accomplished using nitrous acid. The resulting A-nitroso intermediate was reduced with sodium thiosulfate to the corresponding hydrazine, which cyclized to the indazolone. Subsequent alkylation with methyl chloroacetate was followed by hydrolysis to deliver bendazac. 

Fig. 33) had a significant effect at 10 mg/kg, and that 284 could be considered as twice as potent as ( )-hydroxybupropion 277. Thus, Voile et al. showed that the phosphinolactone group might be considered as a biostere of lactol group and used as an unprecedented scaffold for the elaboration of new drug candidates. 

Figure 4.2 Notation of a biosteric transformation for two analogous molecules (top) with their replaceable fragment highlighted by thick bonds (bottom).

In data records of Bioster, two analogous molecule pairs are formally comiected by an arrow like in a chemical transformation (Figure 4.2, bottom). This depiction is not only famUiar to medicinal chemists but is readily adaptable to existing chemical reaction database programs. Obviously, this hypothetical transformation does not correspond to a chemical reaction but cormects two molecules with little atom-atom correspondence. 

While Bioster appears to be without predecessor, several commercial and in-house databases and software tools dealing with bioisosterism and other common replacement techniques have been developed during the past decade (for details, see relevant publications [16-21] and reviews [5, 22-26]). Of the earlier related efforts, the CAVEAT program, based on large structure collections of tricyclic rings (TRIAD) and... 

Bioster 10.1, Digital Chemistry Ltd, Sheffield, UK, http //www.digitalchemistry.co.uk/prod bioster. 

Of the recently developed formalisms reminiscent to Bioster analogue pairs, the somatched molecular pair (MMP) [28] rehes on strictly defined compound pairs that differ only by just one atom or small atomic group. Applying MMP methodology to sets of analogue series retrieved by systematic searching from publicly available bioactivity databases, several common and uncommon bioisosteric replacement pairs could be identified [29]. 

Here we describe the graphic and textual fields on the data record (Figure 4.3), designed for the ISIS /Host version of Bioster 10.1 containing 24 306 analogue pairs and released in November 2010. ... 

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