Introduction
The research chemical market is in a constant state of flux. As more establish compounds are banned, they are quickly replaced with "me-too" drugs. These replacement compounds are chemically similar, but distinct in their pharmacology and pharmacokinetics. They are often inferior (as in the case of the recent methylone replacements) and in addition their unique pharmacology results in unknown and potentially significant toxicology (as in the case of N-(2-methoxybenzyl) derivatized phenethylamines). Current strategies for the development of these analogues typically involves simple changes to prototypical drug structures (carbon chain elongation, N-alkylation, halogen exchange, etc). Little effort has been applied to re-tooling well studied, popular (often illicit) compounds in a way that does not modify their pharmacology or toxicity. Herein we shall exam a more sophisticated approach to analogue design which will focus generally on the synthesis of prodrugs which are converted to the active compound in vivo.
General Theory of Prodrug Design
A prodrug is any compound which, upon introduction to the host system, is transformed into an active drug by either enzymatic or spontaneous processes. The spontaneous processes can occur as a result of a change in pH, oxidative potential, or hydration. Enzymatic processes are not necessarily limited to the host system: microbial flora can produce a diverse array of chemical changes in their environment. In general, the goal of the medicinal chemist is to create a prodrug with increased absorption, more targeted distribution, reduced toxicity, or any combination thereof. It is also important the prodrug does not significantly alter the kinetics of the parent compound. Our goals are slightly different. In general, we would prefer to minimize changes to the parent compound's absorption, distribution, or toxicity and would be willing to accept slight changes in pharmacokinetics. Instead, our chief concern is producing a unique compound not legislated by any government that is stable in ambient conditions (lest it form significant amounts of the parent compound). Optimally, these prodrugs would be easily modifiable to allow the production of new compounds as older ones are legislated. We will achieve this goal by targeted modification of prototypical example compounds: MDA (a primary amine) and MXE (a cyclic ketone).
MXE - Enol trapping
We will first highlight a method unique to ketones that has become more relevant as the ketamine derivatives have become increasingly popular. The strategy involves the formation of the enolate and subsequent trapping with the appropriate reagent. This can be performed in one step utilizing pine needles at reflux, or in two steps utilizing raw buckwheat honey, household ammonia, and that flame-retardant stuff in baby diapers, magnetically stirred. The resulting enol ester (when trapped with a anhydride/chloroformate) or enol carbmate (when trapped with an amide) is rapidly cleaved in vivo by both plasma esterases and in the acidic environment of the gut to yield the parent drug and the free acid/amide.
One can see clearly how this would apply to MXE (Figure 1) in the production of the enol ester (Figure 2). The choice of the R-group would, in an ideal world, be based on in vitro studies of the T1/2 of the prodrug and the Cmax of the parent compound. In reality, it is likely that both the acetyl (R = -CH3) or carbamate (R = -NH2) would be sufficient.
As an aside, it is surprising that current markets have not properly embraced or even tested relevant bio-isosteres for current compound. The oxetane derivative of MXE (Figure 3) would likely provide similar activity to the parent compound. The only important note is the reduced basicity of the adjacent amine due to the electronic influence of the oxetane group itself. In addition, the astute medicinal chemist is likely aware that conjugation of the enol to a more complex NO releasing acid can be used to modulate the parent drug's potency significantly. The synthesis of 4-(nitrooxy)methyl benzoate is fairly straight forward and its conjugation to the enol ether equally so.
(To be continued)
The research chemical market is in a constant state of flux. As more establish compounds are banned, they are quickly replaced with "me-too" drugs. These replacement compounds are chemically similar, but distinct in their pharmacology and pharmacokinetics. They are often inferior (as in the case of the recent methylone replacements) and in addition their unique pharmacology results in unknown and potentially significant toxicology (as in the case of N-(2-methoxybenzyl) derivatized phenethylamines). Current strategies for the development of these analogues typically involves simple changes to prototypical drug structures (carbon chain elongation, N-alkylation, halogen exchange, etc). Little effort has been applied to re-tooling well studied, popular (often illicit) compounds in a way that does not modify their pharmacology or toxicity. Herein we shall exam a more sophisticated approach to analogue design which will focus generally on the synthesis of prodrugs which are converted to the active compound in vivo.
General Theory of Prodrug Design
A prodrug is any compound which, upon introduction to the host system, is transformed into an active drug by either enzymatic or spontaneous processes. The spontaneous processes can occur as a result of a change in pH, oxidative potential, or hydration. Enzymatic processes are not necessarily limited to the host system: microbial flora can produce a diverse array of chemical changes in their environment. In general, the goal of the medicinal chemist is to create a prodrug with increased absorption, more targeted distribution, reduced toxicity, or any combination thereof. It is also important the prodrug does not significantly alter the kinetics of the parent compound. Our goals are slightly different. In general, we would prefer to minimize changes to the parent compound's absorption, distribution, or toxicity and would be willing to accept slight changes in pharmacokinetics. Instead, our chief concern is producing a unique compound not legislated by any government that is stable in ambient conditions (lest it form significant amounts of the parent compound). Optimally, these prodrugs would be easily modifiable to allow the production of new compounds as older ones are legislated. We will achieve this goal by targeted modification of prototypical example compounds: MDA (a primary amine) and MXE (a cyclic ketone).
MXE - Enol trapping
We will first highlight a method unique to ketones that has become more relevant as the ketamine derivatives have become increasingly popular. The strategy involves the formation of the enolate and subsequent trapping with the appropriate reagent. This can be performed in one step utilizing pine needles at reflux, or in two steps utilizing raw buckwheat honey, household ammonia, and that flame-retardant stuff in baby diapers, magnetically stirred. The resulting enol ester (when trapped with a anhydride/chloroformate) or enol carbmate (when trapped with an amide) is rapidly cleaved in vivo by both plasma esterases and in the acidic environment of the gut to yield the parent drug and the free acid/amide.
One can see clearly how this would apply to MXE (Figure 1) in the production of the enol ester (Figure 2). The choice of the R-group would, in an ideal world, be based on in vitro studies of the T1/2 of the prodrug and the Cmax of the parent compound. In reality, it is likely that both the acetyl (R = -CH3) or carbamate (R = -NH2) would be sufficient.
As an aside, it is surprising that current markets have not properly embraced or even tested relevant bio-isosteres for current compound. The oxetane derivative of MXE (Figure 3) would likely provide similar activity to the parent compound. The only important note is the reduced basicity of the adjacent amine due to the electronic influence of the oxetane group itself. In addition, the astute medicinal chemist is likely aware that conjugation of the enol to a more complex NO releasing acid can be used to modulate the parent drug's potency significantly. The synthesis of 4-(nitrooxy)methyl benzoate is fairly straight forward and its conjugation to the enol ether equally so.
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