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  • Introduction of a chloropyridine group

    2022-06-22

    Introduction of a chloropyridine group onto the fluoro derivative (→) leads to a similarly potent compound that exhibits a lower /, and as was observed with (), was rapidly cleared. However, the high clearance of () did not prevent the increase in the concentrations of FAAs even as its plasma levels were rapidly decreasing. Introduction of a chlorine atom to the benzyl ring of the biaryl ether had a significant deleterious impact on the PK properties of () relative to (). The PK profile of () suggested very slow Mirtazapine from the gut was taking place, such that after 4h, compound levels in the plasma and brain were still rising and the / gradually increasing (). Surprisingly, a much smaller effect was observed when the piperazine nitrogen was replaced with a C–H. Compound () gave a / ratio very close to that of . Interestingly, re-introduction of a nitrogen atom into the biaryl ether () had a robust deleterious effect on CNS penetration (/ ratio of 0.45). While lacking a direct comparator for (), it would appear that moving the side-chain of the piperidine ring from the 4- to the 3-position did not benefit CNS penetration. As mentioned above, a strong preference for partitioning into the brain over the plasma is not always necessary for effective target engagement. Using the most CNS penetrant compound () as a reference (), it was determined that residual FAAH activity was reduced to below 10% within a half-hour and remained suppressed throughout the experiment. The profile for the highly potent, but plasma preferring compound (), is somewhat different. Thirty minutes after dosing, () has only inhibited approximately 60% of FAAH present in the brain, but by 1h there is less than 10% active enzyme and by 4h residual activity is below 5%. Even the tetrazole (; / ratio of 0.02:1) is able to inhibit FAAH centrally to below 10% residual enzyme activity but it took approximately 4h to do so. PEA and OEA concentrations began increasing at lesser degrees of FAAH inhibition because they are hydrolyzed by the enzyme more slowly than AEA, which is the preferred Mirtazapine substrate of FAAH. It is possible that AEA levels increased 7–10h post dosing, but data for those time points were not collected. Interestingly, a complete return of enzymatic activity took place by 24 hours post dose, whereas complete reversal of inhibition with the more CNS penetrant took approximately 48h. Mechanism-based enzyme inhibitors don’t necessarily need to exhibit a high / to engage the target, but low concentrations in the brain will affect the rate at which inhibitors and thus the time to onset of pharmacological effect. In those instances where target inhibition is slowly or non-reversible, then it’s possible for the pharmacology induced by the molecule to persist beyond the time it takes for it to be cleared from the organism. For those indications where onset of centrally mediated pharmacology needs to be rapid (such as analgesia), a quickly absorbed compound with a high / ratio may be preferred. For chronic conditions, a compound with a lower / ratio may be preferable in order to minimize the potential for off-target side effects resulting from accumulation of the compound in the brain. Due to recent events in the clinic with BIA 10-2474, it is important to extensively characterize the selectivity and secondary pharmacology of any FAAH inhibitor (particularly a mechanism-based inhibitor) that has the potential to enter the clinic. In addition, while there is the potential for the secondary pharmacology to influence the PK and / ratio of a compound, it is hypothesized that this effect would be minimal. The secondary pharmacology of every compound described in this manuscript has not been studied, but those that have and other compounds within this class of compound were shown to be highly selective after having been extensively profiled (radioligand binding, functional assays, esterase/serine hydrolase enzymatic inhibition assays, and activity-based protein profiling (proteomics)). These data will be included in a subsequent manuscript describing the further characterization of biology and pharmacology of these compounds.