Page 234 - Medicinal Chemistry Self Assessment

Section 4 Whole Molecule Drug Evaluation

Answers

2.25 Sitagliptin

Sitagliptin is an inhibitor of dipeptidyl peptidase IV (DPP-IV), a serine protease that catalyzes the deactivation/degra-
2.25 Sitagliptin
dation of GLP-1. GLP-1 is a 36-amino acid peptide that is responsible for promoting insulin secretion in response to
an increase in blood glucose levels. Currently there are four DPP-IV inhibitors on the market, all of which contain an

essential basic amino functional group that represents the penultimate amino-terminal alanine residue found within
GLP-1. Sitagliptin is an inhibitor of dipeptidyl represents the amino-terminal alanine residue found within GLP-1.

A
F B
F C
NH 2 O D
N
N
N
F N
CF 3
Sitagliptin
Sitagliptin

1. Conduct a structural evaluation of sitagliptin, focusing on the boxed functional groups, and use the infor-
mation in the grid to inform the answers to the questions that follow.
1. Conduct a grid to inform the answers to the questions that follow.
Answer
2. Sitagliptin is group and modify the structure to show the phosphate salt form.
Function
Character Function Amino Acids That

Acidic, Basic, Interaction(s) Can Interact with the
F
Character or Neutral Function Possible with Functional Group via
Name of Hydrophilic F Provide ↑ Solubility Biological Target Ion–Dipole Interactions
NH
2
Functional and/or pK When and/or O at Physiological at pH=7.4
a
Group Hydrophobic Relevant ↑ Absorption pH=7.4 None Is Acceptable
N
N
N
A Halogenated Hydrophilic (F) Neutral Solubility (F) van der Waals Asp, Glu, Lys, Arg
N
aromatic Hydrophobic (R) F Absorption (R) Hydrophobic
hydrocarbon
H-bonding (A) 3
CF
Sitagliptin Dipole–dipole
Ion–dipole (as the
Answer: dipole)
π-π stacking
The pK a the primary amine is the most basic functional group within the structure of sitagliptin.
B Primary amine Hydrophilic (NH ) Basic Solubility (NH ) Ion–dipole (as the Ser, Thr, Tyr, Cys, Asn, Gln,
2 2
Hydrophobic (R) pK 9–11 Absorption (R) ion) Trp, His
a
Ionic
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Sitagliptin phosphate