Page 242 - Medicinal Chemistry Self Assessment

2.26 Sorafenib 231

4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a
starting point, identify which functional groups contribute to the ability of this drug to enter cells via
passive diffusion.
Answer
The halogenated aromatic hydrocarbon, aromatic hydrocarbon, and the pyridine ring carbon atoms
all contribute significantly to the hydrophobic character of sorafenib. It is important to note that
the basic pyridine ring is unlikely to be ionized at physiological pH (pK = 6 < pH = 7.4). Although
a
there appears to be significant hydrophilic character (halogenated aliphatic alkane, urea, ether, the
nitrogen atom of the pyridine, amide) present in this molecule, sorafenib is practically insoluble in
water. The lack of water solubility and clearly identifiable hydrophobic character allows for passive
diffusion of the drug across the cellular lipid bilayer membrane.

5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is
2.4 and 0.8 respectively). Provide a structural rationale for this property difference.

Answer
Based on the information found in the structure evaluation grid for sorafenib, there are several
functional groups that contribute to the overall hydrophobic character of the molecule (e.g., halo-
genated aromatic hydrocarbon, aromatic hydrocarbon, carbon atoms of pyridine/azine ring). Similar
evaluation of nilotinib yields two aromatic rings, a pyrimidine ring (between functional groups D and
E), a pyridine ring (functional group E), and even some hydrophobic character in the histidine ring
(functional group A) that contribute to the overall hydrophobic character of the molecule. When you
compare the sheer number of functional groups that contribute to the overall hydrophobic character
for each drug, nilotinib wins!

6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as a hydro-
chloride monohydrate salt, an inorganic salt. In general, what is the value of each of these types of
salts?
Answer
The value of lipid-soluble organic salts is to decrease the water solubility and increase the lipid solu-
bility of the parent drug (in this case sorafenib) (see Chapter 5 of Basic Concepts in Medicinal Chem-
istry). Typically lipid-soluble salts are used in the formation of lipid-soluble suspensions. In addition,
they can improve the oral bioavailability of acid labile drug molecules and improve the palatability
of liquid solutions. p-Toluenesulfonic acid (tosylic acid) is considered a strong organic acid and forms
a strong counter-ion when dissociated from the drug molecule. Sorafenib is administered as a film-
coated tablet for adults and as a liquid suspension for children.
The value associated with the formation of inorganic salts is due to the improved aqueous solubility,
solvation, and dissolution that results. In general, inorganic salts enhance the absorption of drugs
that are administered orally because they improve both solvation and dissolution properties.