Bioisosteric Motif

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

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. 

Theme 2 recognizes carboxylic acids or bioisosteres of them. There is, however, a gradation of properties of this Motif that range from charged anionic carboxylate-like to uncharged ester-like with an intermediate... 

Luckily, SAR around the amine motif was more fruitful for Vertex. After making many primary, secondary, and tertiary amines, they found that indole was a favorable bioisostere for bis-benzylamine on 2. Testing all possible regioisomers, indole... 

The technique has been extended to the bifunctional class of azasugar phosphonic acids, for example 99, by exploiting the tolerance of rabbit FruA for the bioisosteric phosphonate nucleophile 56 [231]. The resulting heterocycles are a minimum structural motif of glycosyltransferase transition-state analogs. In a strategy inverse of that employed for compound 99, FucA... 

The propellane motif in particular, while an attractive bioisostere, has been limited in use due the significant challenges involved in its synthesis. The group was first introduced as a replacement for the fert-butyl group by Barbachyn and co-workers. Synthetic approaches to propellanes are somewhat limited, and as with the cubanes improved synthetic routes would undoubtedly increase interest in the motif. 

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