Page 143 - Medicinal Chemistry Self Assessment

If there areheld constant and the (*) chiral center is varied. The pair of isomers drawn are diastereomers.

132 Medicinal Chemistry Self Assessment

3. Although aliskiren is administered orally, its oral bioavailability is ~2.5% and is very poorly absorbed.
*
Using the information in the structure evaluation grid, provide a structural rationale for this unfortu-
nate property.
Answer

Oral bioavailability is dependent on the drug’s ability to dissolve in the aqueous contents of the
gastrointestinal (GI) tract and its ability to cross the lipid bilayer membrane. The hydrophilic char-
acter of the drug promotes aqueous solubility. Evaluation of the entire molecule (not just the boxed
functional groups) for hydrophilic character reveals two ethers, two amides, a primary amine (in its
ionized form), and a secondary alcohol that will contribute meaningfully to the hydrophilic character
of the drug. (NOTE: the drug is sold as a hemifumarate salt that further increases the overall water
*
solubility of the drug.) The hydrophobic character of the drug promotes absorption across the lipid
bilayer. Evaluation of the entire molecule (not just the boxed functional groups) for hydrophobic
character reveals an aromatic hydrocarbon, a lipophilic ether, and several aliphatic alkanes. The drug
is formulated as a water soluble salt and had ample hydrophilic character. Unfortunately it does not
have sufficient hydrophobic character to allow for meaningful absorption.

4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It is
4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It is
unknown how much of an absorbed dose is metabolized, and several metabolites from CYP3A4
mediated transformations have been identified. Several possible metabolic products are illustrated.
transformation has occurred and whether or not it represents an oxidative transformation.
Identify which metabolic transformation has occurred and whether or not it represents an oxidative
transformation.

A

B