5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods

5-Substituted-1H-tetrazoles (RCN4H) are often used as metabolism-resistant isosteric replacements for carboxylic acids (RCO2H) in SAR-driven medicinal chemistry analogue syntheses. This review provides a brief summary of the medicinal chemistry of tetrazolic acids and highlights some examples of tetrazole-containing drug substances in the current literature. A survey of representative literature procedures for the preparation of 5-substituted-1H-tetrazoles, focusing on preparations from aryl and alkyl nitriles, is presented in sections by generalized synthetic methods.

5-Substituted 1H-Tetrazoles as Carboxylic Acid Isosteres: Medicinal Chemistry and Synthetic Methods

In the 1970s, a series of observations demonstrated that angiotensin II has deleterious effects on the heart and kidney and that patients with high levels of plasma renin activity are at a higher risk of developing stroke or myocardial infarction than those with low plasma renin activity.1 2 Thereafter, the development of pharmacological probes that block the renin-angiotensin system helped define the contribution of this system to blood pressure control and to the pathogenesis of diseases such as hypertension, congestive heart failure, and chronic renal failure. Thus, the concept of treating hypertension and congestive heart failure by a specific blockade of the renin-angiotensin system was first established with the use of saralasin, a nonselective peptidic antagonist of angiotensin II receptors.3 4 5 6 7 8 9 With saralasin, it became possible to demonstrate that angiotensin II receptor blockade, alone or in combination with salt depletion, lowers blood pressure in hypertensive patients and improves systemic hemodynamics in patients with congestive heart failure.3 4 5 6 7 8 9 10 However, saralasin had many drawbacks. Because it is a peptide, it had to be administered intravenously. This characteristic limited its use to hours or a few days at maximum. In addition, at higher doses, saralasin had some partial agonist, angiotensin II–like effects.

The next major breakthrough in the understanding of the renin-angiotensin system was triggered by the development of orally active angiotensin-converting enzyme (ACE) inhibitors.10 11 12 13 14 15 Studies performed with these agents rapidly confirmed and reinforced the seminal clinical observations made with saralasin. ACE inhibitors are now recognized as an important therapeutic step to control blood pressure in hypertensive patients and to reduce morbidity and mortality in patients with congestive heart failure.16 In addition, because of their ability to lower proteinuria, ACE inhibitors have …

Angiotensin II type 1 receptor blockers.

The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug–target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.

/pdf/carboxylic-acid-bio-isosteres-in-drug-design-1hs3qi7m41.pdf

Carboxylic Acid (Bio)Isosteres in Drug Design

Data on drugs of the tetrazole series published over the last decade are reviewed. The use of tetrazoles as isosteric substituents of various functional groups is examined.

Drugs in the tetrazole series. (Review)

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

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Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy