Heterocycle bioisosteres

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. 

The enantiomers of the dopaminergic, and orally active 6,7,8,9-te-trahydro-jV,A-dimethyl-3 -benz[e]indol-8-amine (54) were studied for their actions on central dopamine and serotonin (5-HT) receptors [123]. The dopaminergic effects were shown to reside in the (- -)-(/ )-enantiomer. Very interestingly, it was shown that racemic (54) and its (- -)-(i )-enantiomer possess potent central 5-HT 1A receptor stimulating properties, which was not reported originally [124]. Still another indication of the trend in DA agonist SAR towards heterocyclic bioisosteres is given by compound (55) [125]. 

Literature data have shown that a phenol or catechol is not essential for binding at the dopamine receptors since a number of non-phenolic compounds possess affinity for the dopamine receptors. Examples of such compounds are pramipexole,155 non-hydroxylated 2-aminotetralins, conjugated enynes, heterocyclic bioisosteres of 3-OH-N-phenylpiperazine,243 and indolylcyclohexanes.244 Recurrent phenomena in all these compounds are a conjugated system and a nitrogen which can be protonated to bind to the receptor. 

Abe et al. reported that the imidazol [l,2-a]pyridine moiety of the basic framework of a class of the non-peptide bradykinin B2 receptor antagonists (11, Figure 15.14) could be successfully replaced by several heterocyclic bioisosteres. Among those, the l-methyl-2-methoxy-l//-benzimidazole, 2-methylquinoxaline and 2-methylquinoline derivatives showed potent B2 binding affinities against both human and guinea pig B2 receptors (Figure 15.14). 

Better bioisosteric design possibilities are provided by quantnm-chemical calcnlations. MaUamo et made use of electrostatic potential surface maps complementarity in defining sulfonyl heterocycles bioisosteric to the steroidal... 

FIGURE 38.2 Carboxylic acid and heterocyclic bioisosteres as solubilizing groups. 

Braeuner-Osbome, H., 1995. Annulated heterocyclic bioisosteres of no-rarecoline. Synthesis and molecular pharmacology at five recombinant human muscarinic acetylcholine receptors. J. Med. Chem. 38, 2188-2195. 

Figure 8.11 Top Two bioisosteres of a phenolic group (Mewshaw, R.E., et al. New generation dopaminergic agents. Part 8 Heterocyclic bioisosteres that exploit the 7-OH-2-(Aminomethyl)chroman D2 template. Bioorg. Med. Chem. Lett. 2002, 12, 271-274.). Bottom Aminoisoquinoline bioisosteres of a benzamidine (Rewinkel, J.B.M., et al. 1-Aminoisoquinoline as benzamidine isosteres in the design and synthesis of orally active thrombin inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 685-690.)...

Mewshaw, R.E., et al. New generation dopaminergic agents. Part 8 Heterocyclic bioisosteres that exploit the 7-OH-2-(Aminomethyl)chroman D2 template. Bioorg. Med. Chem. Lett. 2002, 12, 271-274. 

Anthranilide bioisosteric replacement has also been pursued as a strategy for identifying novel GPR109A agonists. For example, five-membered heterocycles (F) in particular thiophene or furan regioisomers as bioisos-teres of benzene have been disclosed in patent applications by a number of groups (e.g., 23 and 24) [69-72]. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Thiophene-containing molecules can be found in both natural products and synthetic chemotherapeutics. Bithiophene 1, a naturally occurring nematocide, is isolated from the roots of Echinops spaerocephalus, whereas tiaprofenic acid, an anti-inflammatory agent, is a synthetic thiophene derivative. Moreover, thiophene is a useful template for four-carbon homologation via reduction [1], as well as a bioisostere of the benzene ring and other heterocycles in medicinal chemistry. 

Some of the new DA agonists do not suffer from these pharmacokinetic problems. Most of the new compounds have bioisosteric heterocyclic aromatic systems instead of the phenolic ring systems in the older analogues. Some examples of these new agonists will be given here. 

The tetrazole moiety is an excellent bioisosteric replacement for a carboxylic acid, being a small, polar, acidic heterocycle. 

The structure of a catechol itself can be replaced by analogous heterocycles in various derivatives. All these compounds share the ability to chelate metal atoms and to form hydrogen-bonded second rings, the benzimidazole imitates this by way of a covalent ring structure.182 A successful bioisosteric replacement of a phenol or a catechol moiety is the 2-aminothiazolyl moiety. Active dopaminergic compounds which possess such a moiety are B-HT 920 (32)183 and pramipexole (19).146,154,155... 

Selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) give a nice example of bioisosters of heterocycles. The comparison of the most potent selective COX-2 inhibitors (Figure 15.17) suggests that isoxazoles, pyridines, and pyrazoles are good bioisosteres of each other as well as nitrophenol, and indanones. ... 

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