Medicinal chemistry metabolic activation

In response to this biological data, there has been an active interest in the medicinal chemistry community to develop ACC inhibitors for the treatment of metabolic disorders. This chapter begins by briefly describing notable efforts in the ACC literature prior to 2009. The bulk of the chapter focuses on publications and patents that have appeared in 2009-early 2010. Finally, available data showing the efficacy of ACC inhibition in long-term studies is discussed. 

The potential utility of peptides as therapeutics with clinical applications is limited by its metabolic instability or poor transmembrane mobility. Consequently, the preparation of metabolically stable peptide analogs that can either mimic or block the function of natural peptides or enzymes is an important area of medicinal chemistry research. Synthesis of fluoroolefin amide isosteres, its incorporation in peptidomimetics, and the influence of that isosteric substitution on the inhibition of several enzymes such as peptidyl prolyl isomerases, dipeptidyl peptidase IV, and thermolysin is described. Moreover, protein folding and activity... 

Active a-methyl amino acids are of interest in medicinal chemistry. In biochemistry, they are believed to be inhibitors of those enzymes that metabolize the corresponding a-unsubstituted proteinogenic amino acids 7) and they have been found to be constituents in antibiotically active peptides 8). Moreover, if incorporated in a peptide instead of the corresponding proteinogenic amino acid they alter the conformation of the molecule in a certain — sometimes predictable — way. Therefore, they might be useful tools to study the mode of action of a peptide 9 10). 

Adapted from Table VI in Austel B, Kutter R. Absorption, distribution and metabolism of drugs. In Toplis JG, ed. Quantitative structure activity relationships. Medicinal chemistry monographs, vol 19. New York Academic Press 1983. p. 437—96. 

The medicinal chemistry of vitamins is fundamental not only to the therapeutics of nutritional problems but also to the understanding of the biochemical actions of other medicinal agents that directly or indirectly affect the metabolic functions of vitamins and coenzymes. Accordingly, this chapter includes a brief sununary of the basic biochemislry of vitamins, structure-activity relationships, physicochemical properties and some stability considerations, nutritional and therapeutic applications, and brief characterizations of repre.sentative pharmaceutical products. 

A definition of medicinal chemistry was given by a lUPAC specialized commission "Medicinal chemistry concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level. Emphasis is put on drngs, but the interests of the medicinal chemist are not restricted to drugs but include bioactive compounds in general. Medicinal chemistry is also concerned with the study, identification, and synthesis of the metabolic products of these drugs and related compounds. ... 

Although numerous applications of the vinylogy concept are found in the medicinal chemistry literature, only a very few of them are of practical interest, mainly because the preparation of vinylogues usually leads to compounds which are more sensitive to metabolic degradation and more toxic (reactivity of the conjugated double bond) than the parent drug, without being more active. 

Due to important changes in the geometry, vinylogues often have unpredictable activity. For this reason, vinylogues play a minor role in medicinal chemistry. In addition, their metabolic vulnerability or their increased toxicity may represent a significant drawback. 

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