Synthesis and Structure–Activity Relationship Studies ofO-Biphenyl-3-yl Carbamates as Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitors

Abstract

The peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor URB937 (3, cyclohexylcarbamic acid 3’-carbamoyl-6-hydroxybiphenyl-3-yl ester) is extruded from the brain and spinal cord by the Abcg2 efflux transporter. Despite its inability to enter the central nervous system (CNS), 3 exerts profound antinociceptive effects in mice and rats, which result from the inhibition of FAAH in peripheral tissues and the consequent enhancement of anandamide signaling at CB1 cannabinoid receptors localized on sensory nerve endings. In the present study, we examined the structure-activity relationships (SAR) for the biphenyl region of compound 3, focusing on the carbamoyl and hydroxyl groups in the distal and proximal phenyl rings. Our SAR studies generated a new series of peripherally restricted FAAH inhibitors and identified compound 35 (cyclohexylcarbamic acid 3’-carbamoyl-5-hydroxybiphenyl-3-yl ester) as the most potent brain-impermeant FAAH inhibitor disclosed to date.

Structural determinants of peripheral O-arylcarbamate FAAH inhibitors render them dual substrates for Abcb1 and Abcg2 and restrict their access to the brain

“…Compounds bearing a primary or substituted amide in the R 1 position and a hydroxy or a hydroxy-containing group in R 2 (URB937, 5 and 6 )(Fig. 1), although having relative transport ratios similar to those of other test compounds, displayed significantly smaller apical-to-basolateral transport, which correlates with a higher PSA value (≥80Å) and the low brain penetration previously reported for these inhibitors in vivo [15]. Surprisingly, compounds 7 and 8 were effectively transported by Abcg2 (Table 2), even though they were previously shown to readily enter the brain when administered to mice [15].…”

“…These include (i) a primary, secondary or tertiary amide in the meta position of the distal phenyl ring; and (ii) a hydroxy or a hydroxy-containing group in the meta or para position of the proximal phenyl ring (Fig. 1) [15]. To determine whether similar or different features underlie the recognition of these compounds by Abcg2, in the present study we tested a select group of O -arylcarbamate FAAH inhibitors in MDCKII cells overexpressing this transporter.…”

“…PSC-833 (Valspodar) was from Sequoia Research Products (Pangbourne, UK). URB937 and analogs 1–7,9 were synthesized as previously described [12,15]. Compound 8 (cyclohexylcarbamic acid 3′-carbamoyl-6-methylbiphenyl-3-yl ester) was prepared as reported [12].…”

“…Two chemical moieties in the O -arylcarbamate scaffold of URB937 - the hydroxy group in para on the proximal phenyl ring and the amide group in meta on the distal phenyl ring (Fig. 1A) - are important for the exclusion of this compound from the central nervous system (CNS) [12–15]; The role of these two moieties is consistent with the results of ligand-based experiments showing that hydroxyl or amine groups on the outer ring of camptothecin analogs, imidazoacridinones, mitoxantrone and urolithins are essential for substrate recognition and efflux by ABCG2/Abcg2 [9,16–18]. …”

Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors

“…OL-135 is the most well-studied potent and reversible FAAH inhibitor. 4,15,16 Second, irreversible inhibitors, including aryl carbamates, [17][18][19][20] ureas [21][22][23][24][25] and sulfonyl uoride analogues, 26 which form covalent binding with the catalytic site of FAAH, e.g., URB597.…”