Bioisosterism carboxylic acid

Table 2.3 BIOISOSTERIC REPLACEMENTS OF THE C-TERMINAL CARBOXYLIC ACID...

The ionizability of compounds affects other parameters such as solubility, permeability, and ultimately oral bioavailability, so it may be important to track changes in the pka of new compounds. Calculated pka values can be used when planning the synthesis of new compounds, but it is also a good idea to confirm these values experimentally. An example where this strategy can be useful is in the search for bioisosteric replacements for a carboxylic acid group. 

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. 

With respect to the coupling reactions of stannylthiazoles with aryl halides, the union of 4-chlorobromobenzene and 2-tributylstannylthiazole constructed arylthiazole 53 [37]. The Stille reaction of 3-bromobenzylphosphonate (54) and 2-tributylstannylthiazole led to heterobiaryl phosphonate 55, which may be utilized as a substrate in a Wadsworth-Homer-Emmons reaction or a bioisosteric analog of a carboxylic acid [38], The phosphonate did not interfere with the reaction. In addition, the coupling of 5-bromo-2,2-dimethoxy-l,3-indandione (56) and 2-tributylstannylbenzothiazole resulted in adduct 57, which was then hydrolyzed to 5-(2 -benzothiazolyl)ninhydrin [39]. 

One method for preparing imidazolylstannanes is direct metalation followed by treatment with RjSnCl [21]. l-Methyl-2-tributylstannylimidazole, derived in such manner, was coupled with 3-bromobenzylphosphonate (26) to furnish heterobiaryl phosphonate 27 [22], Under the same reaction conditions, 4-bromobenzylphosphonate led to the adduct in 69% yield, whereas only 24% yield was obtained for 2-bromobenzylphosphonate. The low yield encountered for the ortho derivative may be attributed to the steric factors to which the Stille reaction has been reported to be sensitive [23]. Heterobiaryl phosphonates such as 27 are not only substrates for the Wadsworth-Homer-Emmons reaction, but also bioisosteric analogs of the carboxylic acid group. 

Theme 2 recognizes carboxylic acids or bioisosteres of them. There is, however, a gradation of properties of this Motif that range from charged anionic carboxylate-like to uncharged ester-like with an intermediate... 

On the basis of this simple definition he searched for bioisosteres of propionic acid. Using the COSMOfrag database of 28,000 compounds he found several interesting compounds within the top 20 most similar compounds of propionic acid (see Fig. 11.17). While six small carboxylic acids are ranked as most similar to propionic acid, eight non-acidic compounds with quite different chemical skeletons follow, between ranks 7 and 19. Some of them are well known as suitable bioisosters of propionic acid, while the others may be tested as such. 

Bioisosteres can seem strange and nonobvious. For example, a bioisostere for a carboxylic acid is a tetrazole ring. Although a carboxylic acid and tetrazole ring may... 

The Uppsala team then turned their attention to the development of a fast and efficient procedure that allowed conversion of aryl halides to benzoni-triles and aryl tetrazoles by microwave heating. The aryl bromide 11 was subjected to the optimized reaction conditions, which delivered the bis-tetrazole 15 in a two-step yield of 82% (Scheme 8, Kt = 0.56 nM), demonstrating the potential of the method for medicinal chemistry [61]. The tetrazole functionality is one of the most utilized carboxylic acid bioisosteres. 

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

Other interesting new chemistry using bioisosteres is presented in the benzylnitramines of American Cyanamid, the vinylogous ureas of Stauffer, the tetrahydrofuranes of Chevron, and triazinones of FMC. The nitramines of this current example seem to function as a bioisostere of a carboxylic acid. The vinylogous ureas are another example of a possible homologous bioisostere at work. And finally, the triazinones appear to behave as imide bioisosteres. These certainly are concepts which merit wider attention. 

FIGURE 15.21 An example of bioisosterism, or non-classical isoster-ism GABA, isoguvacine, and THIP are all agonists for the GABA-A receptor. The 3-hydroxy-isoxazole ring has a comparable acidity to that of a carboxylic acid function. ... 

The prototypical representatives of the group are the carboxylic acids. However, a huge number of bioisosteres such as sulfonic or phosphonic acids, tetrazoles or 3-hydrox-yisoxazoles are available (see Chapter 15). In addition functions like esters, amides, peptides, aldehydes, primary alcohols and related functions can work as prodrugs or bioprecursors (see Chapter 36). 

FIGURE 38.2 Carboxylic acid and heterocyclic bioisosteres as solubilizing groups. 

Kinney, W.A., Lee. N.E.. Gairison. D.T.. Podlesny. E.J.. Sunmonds, J.T., Bramlett, D., Notvest, R.R., Kowal, D.M., and Tasse. R.P., Bioisosteric replacement of the a-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-l,2-dione containing NMDA antagonists.. /. Med. Chem., 35. 4720, 1992. 

Validated hits were mostly carboxylic acids or bioisosteres (tetrazole, sulfonamides)... 

Scheme 19.28 Potential, new HIV drugs that inhibit Integrase enzyme. Exemplified here is S-1360 96, which is undergoing clinical testing. LE = Lead enhancement where synthesis of numerous analogs eventually led to the next depicted molecule. Note that the keto-acid arrangement in the initial hit proved to be a metabolic liability and needed to be replaced. The three-nitrogen heterocycle has one residual proton that is very acidic, i.e., like a carboxylic acid. It thus serves as a useful bioisostere within this particular molecular context. (With permission from Proudfoot.)...

For every biologically active carboxylic acid, there is a bioisosteric compound in which the carboxyl group is replaced by a tetrazol-5-yl moiety. The tetrazole compounds are degraded biologically more slowly than carboxylic acids. For instance, the tetrazole analogue 11 of nicotinic acid reduces the fatty acid and cholesterol levels in blood. 

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