Phenol bioisosteres

A similar search in the current version of the database retrieved 170 genuine bioisosteric phenol replacements of which 36 selected examples with biological activity data and key references are listed in Table 4.3. 

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Using this analogy, Wu et prepared a series of phenolic bioisosteres of benzazepine D1/D5 antagonists (Figure 15.40). 

Wu, W.-L., et al. Dopamine D1/D5 receptor antagonists with improved pharmacokinetics Design, synthesis, and biological evaluation of phenol bioisosteric analogues of benzazepine D1/D5 antagonists. J. Med. Chem. 2005, 48, 680-693. 

This section describes the application of Bioster database to medicinal chemistry problems. In the first example, the database was helpful in finding replacements for the pharmacologically unfavorable benzodioxole ring. Next, an earlier analysis is updated by tabulated examples of phenol bioisosteres. Finally, selected examples from a fragment query for a-ketoamide bioisosteres are presented. 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de-... 

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. 

A rather distantly related analogue incorporating a e-di-carbonyl moiety as a bioisosteric replacement for a carboxyl, aril done (55), blocks the uncoating of polio virus and herpes simplex virus type I and thus inhibits infection of cells and i,he early stages of virus replication. Thus effective therapy would require careful timing as it does with amantidine. Alkylation of phenol 53 with 1,6-dibromohexane gives haloether... 

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... 

Since it was found that the thienylethylamine moiety might act as a dopamine receptor pharmacophore, we tested whether a thiophene moiety may act as a bioisostere for a phenol in 2-aminotetralins and hexahydronaphthoxazines. Therefore, thiophene analogues of the 2-aminotetralins and hexahydronaphthoxazines, 34-39 were synthesised. All the compounds synthesised were tested in vitro for their affinity at dopamine D2L and D3 receptors. The derivatives with interesting properties were further investigated for their in vivo dopamine receptor activity and bioavailability using the microdialysis technique in freely moving rats.215... 

In conclusion, bioisosteric replacement of a phenol by a thiophene moiety gave dopamine receptor agonists with a lower affinity than the corresponding 2-aminotetralins. This loss in affinity is, however, partly compensated by a relative higher oral bioavailability of the tetrahydrobenzo[ ]thiophenes 34 and 35. 

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. 

In the present study, a series of thiophene analogues of 2-aminotetralins and hexahydronaphthoxazines were studied in vivo for their ability to decrease striatal dopamine release, their effects on locomotor activity, and their behavioural characteristics in reserpinised rats, in order to investigate whether a thiophene moiety can act as a bioisostere for the phenol moiety. 

Our results suggest that the thiophene moiety can act as a bioisostere for a phenol group in hydroxylated 2-aminotetralins. For the hexahydrothianaphthoxazines it was not possible to discriminate between bioisosterism for a phenyl or a phenol moiety. The tetrahydrobenzo[ ]thiophenes could be used as lead compounds for the development of novel dopamine receptor ligands with improved relative oral bioavailability. 

Using microdialysis experiments the relative oral bioavailabilities of the compounds 34, 35, 11, 80, 12, 83 and 9 could be calculated. These data show that a compound with a catechol or a phenol possesses a low relative oral bioavailability (compounds 11, 80, 12 and 9). To circumvent such a low relative oral bioavailability a bioisostere of a phenol could be introduced or a prodrug approach could be applied. Compounds 34 and 35 are examples of a bioisosteric replacements and compound 83 is a prodrug of a catecholic or a phenolic 2-aminotetralin. Both types of compounds show an improved relative oral bioavailability, as compared to the... 

FIGURE 15.39 Bioisosteric replacements of the phenol function in the design of W-methyl-D-aspartate (NMDA) receptor antagonists. 

FIGURE 15.61 An example of bioisosterism, or non-classical isoster-ism, the methylsulfonamide substituent has comparable acidity to the phenolic hydroxyl group. ... 

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