The Bioisosteric Substitution

There are many examples of each of these possibilities (see figure 8.8). In the case of the 2 sugar position, most of the 2 -substititutions have been achieved with 2 -0-alkyl, 2 -amino, and 2 -fluoro replacements. Purine base substitutions have been performed with 2-aminopurine, xanthosine, and isoguanosine. Phosphodiester replacements have been effected using phosphorothioate substitutions. As for the non-nucleotide linkers, propanediol linkers have been employed. Using these various bioisosteric substitutions,... 

Another interesting switch consisted in the progressive passage from desmethyl-minaprine 6 to the bioisosteric thiadiazole 7 (Fig. 1.19), and then to the bioisos-teric thiazoles. Tri-substitution on the phenyl ring and replacement of the aliphatic morpholine by a pyridine led to compound 8 which exhibited some affinity for the receptor of the 41 amino-acid neuropeptide CRF. Further optimization led to nanomolar CRF antagonists such as 9 [41,42]. 

No two substituents are exactly alike. Any substitution impacts size, shape, electronic distribution, lipophilicity, pKa, chemical reactivity, susceptibility to metabolism, and the like. The bioisosteric approach is the total change induced by substituent replacement on the potency, selectivity, duration of action, bioavailability and toxicity, of an agrochemical. The following groups are examples of... 

Bioisosteric substitutions are a commonly used strategy in medicinal chemistry drug design as an approach to enhance the desired biological or physical... 

To demonstrate the generality of this bioisosteric equivalence, the same group applied the same substitution to 9, a factor Xa inhibitor that yielded 10. Compound 10 reflects the same loss in potency that was observed for 8 towards 7, but reoptimization of the Af-acyl group afforded quickly a significant gain of potency. 

It is, however, pertinent to mention here that the ester as well as the N-substituted functional moieties are nothing but bioisosteres as illustrated below and it further expatiates and justifies the strategical presence of such groups in almost identical locations in the various tailor-made structurally designed local anaesthetics. 

The simplest application of the bioisostere approach to build in structural novelty would probably lie in the substitution of a single atom by one not covered in existing patents, although changes this small run the risk of being considered obvious by patent examiners. 

Scheme 1.3 Structures of the clinical HDAC inhibitor Vorinostat and of ferrocene derivatives that have been designed by bioisosteric substitution of the aromatic moiety.

Pertinently substituted -triazines are known to inhibit PS II electron flow in chloroplasts and are herbicidal [20], and also phenylurea and carbamate herbicides are known to act at the same site as that of 5 -triazines [17]. In other words, they are bioisosters to each other with respect to the binding to the action site, or the bioisosterism between them is fairly high, irrespective of the apparently different structures. Moreover, phenylureas are known to have cytokinin activity [4,6]. Thus, the carbamates are expected to behave bioisosterically to phenylureas or 5 -triazines with respect to the interaction with the cytokinion receptor. 

Based on the bioisosterism, the salts of alkylphosphonates lA or IC were assumed to have a more powerful inhibitory effect against plant PDHc El and better h iddal activity than the corresponding alkylphosphonates, because sodium D-methyl acety-Iphosphonate 1-1 has been reported as a powerful PDHc El inhibitor [1]. Five series of novel alkali metal salts of D-alkyl 1-(substituted phenoxyacetoxy)alkylphosphonates IIA-IIE were first designed as potential plant PDHC El inhibitors. IIA-IIE could be easily synthesized from corresponding D,D-dialkyl 1-(substituted phenoxyacetoxy) alkylphosphonates lA or IC in one step. It was also expected that 1-(substituted phenoxyacetoxy)alkylphosphonic acids (Scheme 3.2) could have better herbicidal activity, because they were more analogous to pymvic acid which acted as the substrate of PDHc. However, 1-(substituted phenoxyacetoxy)alkylphosphonic acids were not stable for long-time storage. 

To improve relevant pharmacokinetic parameters i.e. oral absorption, metabolism and renal excretion of FimH antagonist lb), we focused on three approaches. First, the molecular planarity and symmetry of the biphenyl aglycone was disrupted by modifying the substitution pattern (Fig. la). Second, the hydrophobicity was improved by heterocyclic biaryl aglycones (Fig. lb). Finally, oral availability was improved by replacing the carbojq lic acid by the bioisosteric cyano group (Fig. lc). ° ... 

It was mentioned above that both citalopram, and its (S)-enantiomer have SSRI properties. Inspection of Figure 18.28 shows that slight modifications give talo-pram, which is a potent NARI, despite the stmctural similarity to citalopram. Both share the phenyl substituted phthalane (1,3-dihydroisobenzofuran) and propylamine moiety. Talopram may therefore be viewed as a secondary amine derivative of citalopram after removal of the two aromatic substituents and attachment of a 1,1-dimethyl group to the 3 position. The NARI property, however, remains when the oxygen is replaced with an isosteric sulphur atom. This provides talsupram, the thiophthalane (l,3-dihydrobenzo[c]thiophene) derivative of talopram, which is a bioisostere. 

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]. 

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