Urea bioisosteres

FIGURE 15.37 Binding affinities for various urea bioisosteres acting as antagonists at the NPY Y] receptor. 

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. 

In a smdy undertaken on antagonists of the dihydropyridine neuropeptide Yi receptor, common bioisosteres such as thiourea and cyanoguanidine were examinated as urea replacement (Figure 15.37) and also more uncommon derivatives like squaric acid and thiadiazole oxide. 

Among more exotic surrogates, the 3,4-diamino thiadiazole dioxide moiety was proposed as a weakly acidic urea equivalent (Figure 15.38). The similar thiatriazole dioxide is found in the H2 antagonist tuvatidine (HUK 978). Other bioisosteres are exo-endo amidinic heterocyles bearing an electron-attracting function in the a position (Figure 15.38). 

In the histaminic H2 receptor antagonist series, the classical urea-thiourea-guanidine progression was successfully completed by the use of the V-nitro and V-cyanoguanidines and, later on, by l,l-diamino-2-nitroethylene groups (Fig. 13.19). Cyano amidines and carbamoyl amidines were also used, and structure-activity relationship patterns were rationalized in terms of dipole moment orientation of related bioisosteric groups. ... 

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