Phenyl/pyridine bioisosteric replacement

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

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]. 

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. 

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