Prodrugs of Amines

The presence of an amino group can affect a drug's physicochemical and biological properties in several ways. These include (1) intermolecular or intramolecular aminolysis leading to reactive and/or potentially toxic substances, (2) solubility problems when the drug is present with another ionizable functionality such as COOH (zwitterionic nature under physiological pH, potentially limiting its dissolution rate and/or its passive permeability), and (3) terminal free amino acid groups providing recognition sites for proteolytic enzymes, such as aminopeptidase and trypsin, present in the gastrointestinal tract lumen, the brush border region, and the cytosol of the intestinal mucosa cells. For all these reasons, prodrug approaches have been advocated for improving in vivo behavior of active compounds containing amino groups. Amides Because of the relatively high stability of amides in vivo, N-acylation of amines was formerly of limited use in prodrug design. Only a few examples of simple amide prodrugs are known that are sufficiently labile in vivo; these include the N-l-isoleucyl derivative of dopamine46 and the N-glycyl derivative midodrine.47,48 With the use of proteases as prodrug-converting enzymes, amines can be coupled to peptide carboxylates, resulting in amide bonds cleavable by proteases (e.g., 34).

Midodrine (79) is a glycinamide prodrug, and the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine (78), an a-agonist formed by deglycination of midodrine. Midodrine is rapidly absorbed after oral administration. The plasma level of the prodrug peaks after about half an hour, and declines with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% and is not affected by food. Approximately the same amount of desglymidodrine is formed after intravenous and oral administration of midodrine. Midodrine has been used successfully in the treatment of neurogenic orthostatic hypotension and, more recently, in the treatment of dialysis hypotension. It acts through vasoconstriction of the arterioles and the venous capacitance vessels, thereby increasing peripheral vascular resistance and augmenting venous return, respectively. The prodrug is a unique agent in the armamentarium against orthostatic hypotension since it has minimal cardiac and central nervous system (CNS) effects.47,48 N-a-Acyloxyalkoxycarbonyl Derivatives Carbamates are of limited use in prodrug design due to their general resistance to enzymatic cleavage in vivo. The introduction of an enzymatically labile ester group in the carbamate structure could render them sensitive to esterase-catalyzed hydrolysis leading to activation. Thus, N-a-acyloxyalkoxycarbonyl derivatives (80) of primary and secondary

ACD/LogD ACD/LogP pH 7 pH 1 R = H 0.378±0.279 -1.14 -3.42


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