Bioisosteric relationships

The preceding discussion on isosterism dealt mainly with the types of isosteres that may be considered classic (i.e., that is where the molecule bears a more or less readily apparent structural relationship to the parent compound). If one interprets bioisosteric relationships more broadly, less readily apparent similarities may result in useful new drugs. These might aptly be considered nonclassic isosteres. 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

In the optimisation process, we realized that the concept of bioisosterism and the available data for quantitative structure-physical property relationships were potentially a great help to pursue the optimisation effectively. But at the same time I should mention that even if comprehensive lists of bioisosteres and physicochemical parameters of... 

Two other publications on the bioisosteric replacement of pyridine show similar results. The first paper reports the study of bioisosteric potential of diazines in the field of combined antithrombic thromboxane A2 synthetase inhibitors and receptor antagonists. On the basis of the structure-activity relationships (SAR) observed in this study, it turned out that only the 2-pyrazinyl, 4-pyridazinyl... 

Depreux, P, Lesieur, D., Mansour, H. A., Morgan, P, Howell, H. E., Renard, P., Caignard, D. H., Pfeiffer, B., Delagrange, P, Guardiola, B. et al. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J. Med. Chem. 1994, 57(20), 3231-3239. 

The oxyacetic acid residue of the monoxacetams is bioisosteric with the sulfate moiety of the monosulfactams. In addition, the presence of the carboxylate moiety provided opportunity for the preparation of esters that could act as orally absorbed prodrugs. Based on structure-activity relationships, SQ 82,291 (45) [90898-90-1]y C12H15N506S, the nonacidic methoxime side chain of which was necessary to maintain oral absorption of the prodrugs, was prepared. SQ 82,291 has a high, specific affinity for the PBP-3 transpeptidase of gram-negative bacteria. However, it lacks the isobutyric acid moiety of aztreonam (17) on the oxime residue and whereas the activity of SQ 82,291 vs the Enterobacteriaceae was maintained, antipseudomonal activity was significandy diminished (37). 

Bioisosteric interchanges, of course, are not limited to univalent functions. In fact, divalent atoms and groups add the additional factor of steric similarity to the equation since the bond angles between the valencies are very similar. The angles for/CH2 (l 11.5°),/NHv(l 11°) /S (l 12°), and/Q(108°) illustrate this point. When a deviation of 3 degrees, depending on the full structural features of the compound, are taken into consideration, it becomes apparent how identical these features can be. A rather convincing example is seen when the bioactivity relationship between the isosteric ester and amide moieties is examined (Fig. 1-4). 

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. ... 

Fig. 5. The relationship between struetures, M2/M1- and M-agonist indiees, >K values and pharmaeokinetie properties of areeoline and a number of isoxazole bioisosteres.

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