Page 172 - Medicinal Chemistry Self Assessment
P. 172

2.13   Dabigatran Etexilate        161
                                     Chapters 1.13/2.13 (removed bolded text)



                                         A          B                        E          F
                                                              D





                                             C




                                                      Active form of Dabigatran


                 2.  Dabigatran etexilate is a non-peptidomimetic prodrug. Provide a brief rationale for the value of

                    converting an active drug into a prodrug.
                                     Chapters 1.13/2.13 (removed bold drug name)

                    Answer
                    There are situations (e.g., the need to enhance water or lipid solubility) when it is therapeutically

                    beneficial to administer drug molecules that have been covalently modified to produce inactive (or
                    very weakly active) analogs (i.e., prodrugs) (see Chapter 5 in Basic Concepts in Medicinal Chemistry).
                    Bioactivation of these prodrugs via rapid metabolic transformation (e.g., ester hydrolysis) can occur
                    via chemical or enzymatic mechanisms. Typically metabolic activation (via hydrolysis) occurs within
                    the gastrointestinal (GI) tract. Given that esterases are ubiquitous, release of the active drug can
                    occur in the plasma or even at the target tissue.
                    In the case of dabigatran etexilate, a carboxylic acid is converted to an ester and an amidine is
                    converted to a carbamate. In both cases, the modified functional group is significantly more lipid
                    soluble than the parent functional group. Dabigatran is not absorbed orally, so it is necessary to
                    develop a prodrug analog to allow for sufficient absorption from the GI tract.


                 3.  Dabigatran etexilate rapidly undergoes two esterase-catalyzed hydrolytic reactions to the active drug
                                                         Dabigatran etexilate mesylate
                    dabigatran. Show the products from each of the esterase-catalyzed hydrolytic reactions that occur in

                    the plasma.
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