Page 207 - Medicinal Chemistry Self Assessment

Answer:
A sodium salt is an ility o the indole ring.

A O O –
B
OH
S H 3 C CH 3
Cl N
196 Medicinal Chemistry Self Assessment
C C A

H 3 CO O CH 3
Montelukast
O
4. Montelukast and zafirlukast exert their mechanism of action by interacting with cysteinyl leukotriene
B
–
receptors and blocking the normal actions of endogenous leukotrienes (LTC , LTD , and LTE ). It has
N
4 S
4
4
been proposed that this interaction requires five key elements: an ionic interaction, a hydrogen bond
H
O
O
N
interaction where the antagonist acts as the acceptor, as well as the interaction of the antagonist
with three separate hydrophobic pockets within the receptor. Using this information and the struc-
O
tures of montelukast and zafirlukast, propose potential binding interactions between these drug
Zafirlukast
N
molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a physi-
ological pH=7.4. CH 3
Answer

Let us evaluate these two drug molecules separately. The structure of montelukast contains a carbox-
ylic acid that could participate in an ionic bond with the leukotriene receptors. It also contains two
4. Montelukast and. Assume that all binding interactions occur at a physiological pH of 7.4.
functional groups, the tertiary hydroxyl group and the aromatic heterocyclic amine, that could
Answer:
participate in a hydrogen bonding interaction as an acceptor. As shown below, the structure of
montelukast contains four separate regions that could interact with the three hydrophobic pockets
Let us four nd hydrophobic interactions.
of the receptor via van der Waals and hydrophobic interactions.

The four boxed areas could interact with a Ionic bond
hydrophobic pocket within the leukotriene receptors.
Hydrogen bond
(as acceptor)

Hydrogen bond
(as acceptor) Montelukast

Similarly, the structure of zafirlukast contains a sulfonamide group that could participate in an ionic

interaction with the leukotriene receptor, as well as two functional groups, the methoxy group and

the carbamate, that could participate in a hydrogen bonding interaction as an acceptor. As shown
below, the structure of zafirlukast also contains four separate regions that could interact with the
Similarly, the structure of group that could participate in an ionic bond with the leukotriene.

three hydrophobic pockets within the receptor.

Hydrogen bond
(as acceptor)

The four boxed areas could interact with a
hydrophobic pocket on the leukotriene receptors.

Ionic bond

Hydrogen bond Zafirlukast
(as acceptor)

5. Calculated log P values of montelukast or be primarily excreted unchanged?

6. Shown below is the to perform with zafirlukast.

Answer:

A. Methylation: No., this metabolic transformation cannot occur.
B. Aromatic Oxidation: Phase I; Yes

Note: Aromaric hydroxylation
could also occur on this
ring; however, it is more
sterically hindered.