A novel monoacylglycerol lipase inhibitor with analgesic and anti-inflammatory activity

Abstract

A variety of long chain 1,2-diamines and related compounds were synthesized and tested for their activity on fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MGL). (2S,9Z)-Octadec-9-ene-1,2-diamine selectively inhibits MGL (K(i) 21.8 microM) without significantly affecting FAAH. This compound exhibited interesting in vivo analgesic and anti-inflammatory properties, suggesting that selective inhibitors of MGL may be valuable novel agents for the treatment of inflammatory pain.

Figure 1

The most important endocannabinoids.

Figure 2

Inhibitors of monoacylglycerol lipase.

Figure 3

In vivo analgesic activity of inhibitors 21 and 22. Control (■), 22 (3.6 mg/kg, ◆), 21 (3.6 mg/kg, ▴), 22 (36 mg/kg, ●), 21 (36 mg/kg, ×), aspirin (200 mg/kg, +).

Scheme 1

Synthesis of 2-oxoamide 12. Reagents: (a) CH₃(CH₂)₁₃CHOHCOOH, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, HOBt, Et₃N, CH₂Cl₂; (b) AcNH-TEMPO, NaOCl, NaBr, EtOAc=PhCH₃=H₂O; (c) 50% TFA=CH₂Cl₂.

Scheme 2

Synthesis of 1,2-diamines 21 and 22. Reagents: (a) EtOOCCH=CHCH₂P(=O)(OEt)₂, LiOH, THF; (b) H₂, 10% Pd/C, Boc₂O, MeOH; (c) DIBALH, Et₂O; (d) C₉H₁₉P⁺Ph₃Br⁻, KHMDS, toluene; (e) 4 N HCl/Et₂O.

Scheme 3

Synthesis of diamines 25a and 25b. Reagents: (a) R¹P⁺Ph₃Br⁻, KHMDS, toluene; (b) H₂, 10% Pd/C, Boc₂O, MeOH; (c) 4 N HCl=Et₂O.

Scheme 4

Synthesis of carboxamide 29. Reagents: (a) Boc₂O, Et₃N, MeOH; (b) DCC, HOBt, 25% aq:NH₃, CH₂Cl₂, DMF; (c) 4N HCl/Et₂O.