Phenyl/pyridine bioisosteric

Figure 2.5 Phenyl/pyridine bioisosteric replacement leading to clinical candidate BMS-488043.

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

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]. 

Isoxazole and Isothiazole Derivatives. Bioisosteric replacement of the pyridine ring in nicotine generated a series of novel isoxazole compounds that are selective and potent neuronal nAChR agonists, as exemplified by ABT-418 (71) (Table 14.8) (299). Among the variety of substituents examined at C3 cf the isoxazole, methyl turns out to be optimal, even though other substituents, such as C2-C4 linear alkyl, CF Br, and benzyl (not phenyl), still provide potent analogs. The 3-des-methyl... 

A-(6-Chloronaphthalen-2-)sulfonylpiperazine derivatives 4 and 5 (Figure 15.12) are potent factor Xa inhibitors. Haginoya et al proposed to replace the pyridine-phenyl or the pyridine-piperidine residue by a fused-bicyclic ring which contains an aliphatic amine and a pyridine to yield the compound 6 that has an interesting factor Xa inhibitor activity. The bioisosteric replacement of the pyridine moiety of the 6-methyl-5,6,7,8-tetrahydro-[l,6]naphthyridine by phenyl, thiophene, or thiazole analogs yielded analogs with similar or better antifactor Xa activity, but also to conserve a moderate bioavailability. 

The replacement of a nitrile with a carboxylic acid group is the least detrimental transformation, and is an example of an atypical bioisosteric replacement. Moreover, there are a few others that add polarity to the molecule, such as methyl to methyl amide, addition of a isobutyric acid, 1,2-phenyl to 2,3-pyridine, and 2,3-pyridine to 2,3-pyrazine groups. Interestingly, the substitution of a methyl with an exotic trifluoromethyl ether moiety [34] is bioisosteric, even though there is a considerable increase in lipophilidty. This is also the case for the replacement of the more metabolically labile isopropyl ether with the cydopropyl group. Finally, a little considered bioisosteric transformation is 2-thiophene to para-fluorophenyl, which has been very recently proposed in a large-scale MMP analysis [35]. 

Paths 1 and 2 of Fig. 2 represent simplistic but descriptive manifestations of the SAR logic. However, the pyridine for phenyl substitution example (path 3) can optimize properties such as aqueous solubility due to the incorporation of a polar atom, in this case nitrogen. And finally, path 4 represents the important SAR concept of bioisosterism in which substitutions can be rationally made based on electronic structure and atomic size of functional groups and have literature precedent for activity enhancement for example, the thiophene for phenyl substitution in path 4 [35]. Another valuable example of bioisosterism is the fluorine for hydrogen substitution which has successfully aided numerous probe and drug development programs [36]. 

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