Catechol bioisosteres

Htibner, H. Haubmann, C. Utz, W. Gmeiner, P. (2000) Conjugated enynes as nonaromatic catechol bioisosteres synthesis, binding experiments, and computational studies of novel dopamine receptor agonists recognizing preferentially the D3 subtype. J. Med. Chem. 43, 756-762. 

Catechol bioisosteres are often utilized to overcome pharmacokinetic and toxicological issues linked to this moiety. SuccessfiJ examples of bioisosteric replacement of catechols can be found in catecholamines. Benzimidazole analogues of the adrenergic agonists norepinephrine and isoproterenol (Figure 2.10) were... 

Because of its bioisosteric similarity to the normal physiological substrate L-dopa (4), L-mimosine (5) inhibits catechol oxidation by the enzyme tyrosinase (7). These compounds exemplify a situation in which bioisosteresdis-play opposite pharmacologic effects at the same receptor. 

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... 

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. 

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... 

A recent case described the synthesis of more stable bioisosteres of inhibitors of the insulin-like growth factor-1 receptor kinase (Figure 15.43). Based on the structure of AG 538 ° which contains two catechol rings and is sensitive to oxidation in cell, a new series of kinase inhibitors were developed. The catechol moiety was replaced by a benzoxazolone ring resistant to oxidation yielding two compounds GB19 and AGL2263 which maintain same potency as AG 538. 

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