2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity

Abstract

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic substituents limiting their availability. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, a new series of benzohomoadamantane-based amides were synthetized, fully characterized, and evaluated as sEHI. Most of these amides were endowed with excellent inhibitory potencies. A selected compound displayed anti-inflammatory effects with higher effectiveness than the reference sEHI, TPPU.

Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

“…1 H NMR (400 MHz, CDCl 3 ): δ 1.17 [dq, 2H, J = 12.0 Hz, J′ = 4.0 Hz, 3′(5′)-H ax ], 1.56 [t, 2H, J = 10.8 Hz, 3″(5″)-H ax ], 1.76−2.00 [complex signal, 7H, 10(13)-H ax , 6( 12)-H ax , 3″(5″)-H eq , 3′-H eq or 5′-H eq ], 2.02−2.20 [complex signal, 5H, 10(13)-H eq , 6( 12)-H eq , 5′-H eq or 3′-H eq ], 2.21 (d, 2H, J = 6.0 Hz, 8-H 2 ), 2.65−2.80 (complex signal, 2H, 4″-H, 2′-H ax or 6′-H ax ), 3.11 (t, 1H, J = 12.4 Hz, 6′-H ax or 2′-H ax ), 3.21 [broad signal, s, 2H, 5(11)-H], 3.43 [t, 2 H, J = 11.2 Hz, 2″(6″)-H ax ], 3.75 (m, 1H, 4′-H), 3.83 (d, 1H, J = 13.2 Hz, 2′-H eq or 6′-H eq ), 3.99 [dd, 2H, J = 11.6 Hz, J′= 2.0 Hz, 2″(6″)-H eq ], 4.47 (d, 1H, J = 14.0 Hz, 6′-H eq or 2′-H eq ), 4. [9]annulen-7-yl)-3-(1-(cyclopropanecarbonyl)piperidin-4-yl)urea (22). To a solution of 9-fluoro-5,6,8,9,10,11hexahydro-7H-5,9:7,11-dimethanobenzo [9]annulen-7-amine hydrochloride (150 mg, 0.56 mmol) in DCM (4.5 mL) and saturated aqueous NaHCO 3 solution (3.5 mL), triphosgene (61.5 mg, 0.21 mmol) was added.…”

“…The assays for the in vitro determination of the inhibitory activities toward human and mouse sEH, 30 the assays for determination of the PAMPA−BBB permeability, 36 aqueous solubility, cytotoxicity in SH-SY5Y cells, microsomal stability, cytochrome P450 inhibition, permeability, hERG inhibition, and inhibition of human LOX-5 were carried out following described methodologies previously used in our group (see the Supporting Information for complete details). 21,22 4.3. In Silico Studies.…”

“…Although most of these amides retained or even improved the inhibitory activity of their urea counterparts at the human and mouse enzymes (e.g., compound 7, Figure 2), only moderate improvements in microsomal stabilities were found. 22 Herein, we report further medicinal chemistry around inhibitor 5. New piperidine derivatives retaining the urea group as the main pharmacophore, different substituents in the C-9 position of the polycyclic scaffold (R in I), and a broad selection of substituents at the nitrogen atom of the piperidine (R′ in I) were synthesized (Figure 2).…”

“…Later on, in an effort for improving the DMPK properties of piperidine 5 , we designed a series of analogues where the urea core was replaced by an amide group. Although most of these amides retained or even improved the inhibitory activity of their urea counterparts at the human and mouse enzymes (e.g., compound 7 , Figure ), only moderate improvements in microsomal stabilities were found …”

“…Although most of these amides retained or even improved the inhibitory activity of their urea counterparts at the human and mouse enzymes (e.g., compound 7 , Figure 2 ), only moderate improvements in microsomal stabilities were found. 22 …”