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    • In the course of an internal FAAH program many

    2021-10-18

    In the course of an internal FAAH, program,, , , , , , , , , , , , , many very similar compounds were profiled in vivo with particular interest paid to their ability to penetrate the BBB. The compounds profiled were heteroaryl piperazinyl and piperadinyl ureas; a class of compounds, reported on previously by us and others (),, , , , that inhibit the FAAH enzyme through forming a covalent adduct between the active site serine (Ser241) and the urea carbonyl with the concomitant loss of the aryl amine. The compounds are synthetically modular and most are easily prepared in a few steps (see ). contains a selection of data generated from compounds on which only the heteroaryl amine was varied. Included in the table are the in vitro potency of the molecules reported as apparent ICs (due to the time dependent nature of the inhibition), PK data from Sprague–Dawley rats when available, the calculated topological polar surface areas (TPSAs) and Log values, and the brain to plasma ratio of compound concentrations (/) obtained after dosing of the compound by oral gavage. Interestingly, the range of / ratios obtained was quite broad and they did not correlate with TPSAs or ps. Likewise, the Log values for these compounds (ranging from 2.8 to 4.9) did not offer a predictive trend with regard to brain penetration. The simple phenyl derivative () serves as a reference point and its / ratio was an impressive 3.64. It has been reported that the presence of pyridine nitrogens in a molecule tends to lead to decreased brain penetration relative to phenyl., , In the present series of molecules, replacing the phenyl with a 3-pyridyl group to give () modestly decreased CNS penetration to give a / ratio of 2.62. While retained excellent brain penetration properties, simply adding a chlorine Diclofenac to the 4-position of the pyridine ring () led to a significantly lower / ratio. Addition of the chlorine atom also appears to have introduced greater metabolic instability as () had a 4-fold higher rate of clearance than . Counterintuitively, the 4-cyano pyridine derivative () actually had a higher B/P ratio than , although it too gets cleared rather quickly. The non-basic pyrazine derivative () exhibited the highest / ratio (4.2:1) of any of the compounds in this data set despite having two azine nitrogen atoms. The greatest variation in B/P ratios was obtained with 5-membered heteroarenes. The simple 3-isooxazole derivative () is highly brain-penetrant (/ ratio of 3.3), but replacement of the oxygen with a hydrogen-bond donating N–H results in a compound only slightly favoring partitioning into the brain over the plasma. Perhaps not surprisingly, the tetrazole (), which would be completely deprotonated under physiological conditions (tetrazole p≈4.9, >99% deprotonated at pH 7.2), is the least brain penetrant compound of this series with a / of 0.02:1 (/ of >45:1). However, the very poor CNS penetration ability of () does not preclude effective central target engagement (vide infra). Hydrogen-bond donating and acidic groups are not the only chemical features that lead to decreased brain penetration. Fusion of a benzo ring to the isoxazole to give () also leads to a large decrease in the / ratio, greater in fact, than replacement of the oxygen with an N–H. The two imidazopyridine derivatives ( and ) are interesting cases as they are significantly protonated at physiological pH (imidazopyridine p≈6.8, 60% protonated at pH 7.2). These compounds favor the plasma over the brain by about 3:1 and, at least with (), appear to be cleared quickly. This compound too, should serve as a reminder that high volumes of distribution as obtained from simple PK experiments, in this case =10.7, does not necessarily predict good brain penetration. We have been able to affect large changes in the CNS penetrating ability of these ureas simply through the modification of the pendant heteroarenes of the urea, but we can also modulate / through small changes to the piperazine core and the biaryl ether tail (). Replacement of the chlorine atom of with a bromine (), fluorine () or CF () group leads to a modest reduction in /. Introduction of a chloropyridine group onto the fluoro derivative () leads to a substantial further decrease of /, and as was observed with (), gave a compound that was rapidly cleared.