Anthranilic acid-based inhibitors of phosphodiesterase: Design, synthesis, and bioactive evaluation

Abstract

Our previous studies identified two 2-benzoylaminobenzoate derivatives 1, which potently inhibited superoxide (O(2)˙(-)) generation induced by formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) in human neutrophils. In an attempt to improve their activities, a series of anthranilic acid derivatives were synthesized and their anti-inflammatory effects and underlying mechanisms were investigated in human neutrophils. Of these, compounds 17, 18, 46, 49, and 50 showed the most potent inhibitory effect on FMLP-induced release of O(2)˙(-) in human neutrophils with IC(50) values of 0.20, 0.16, 0.15, 0.06, and 0.29 μM, respectively. SAR analysis showed that the activities of most compounds were dependent on the ester chain length in the A ring. Conversely, a change in the linker between the A and B ring from amide to sulfonamide or N-methyl amide, as well as exchanges in the benzene rings (A or B rings) by isosteric replacements were unfavorable. Further studies indicated that inhibition of O(2)˙(-) production in human neutrophils by these anthranilic acids was associated with an elevation in cellular cAMP levels through the selective inhibition of phosphodiesterase 4. Compound 49 could be approved as a lead for the development of new drugs in the treatment of neutrophilic inflammatory diseases.

Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

“…The drug HFP034, butyl 2-[2-(2-fluorophenyl) acetamido] benzoate, was derived from anthranilic acid derivatives and exhibited potent inhibitory activity on PDE4 enzyme (IC 50 = 4.2 μM) and fMLP-induced generation of in human neutrophils in vitro (Cheng et al, 2011 ). The drug HFP034 was found to be well-absorbed into the skin and, meanwhile, causes negligible irritation on healthy skin.…”

Topical application of anthranilate derivatives ameliorates psoriatic inflammation in a mouse model by inhibiting keratinocyte‐derived chemokine expression and neutrophil infiltration

“…HFP031 (in our previous study) showed dual inhibitory effects on human neutrophil elastase and proteinase 3 (19). HFP034 (in our previous study) exhibited a potent inhibitory effect on the N-formyl-Lmethionyl-L-leucyl-phenylalanine-induced release of O 2 ×2 and phosphodiesterase (PDE)4 activity by using human neutrophils as the inflammation cell models (20). PDE4 is a cAMP-metabolizing enzyme, exhibiting a major role in inflammatory regulation.…”

Pharmacokinetics, biodistribution and toxicology following intravenous and oral administration of DSM-RX78 and EFB-1, two new 2-(2-fluorobenzamido)benzoate-based PDE4 inhibitors, to rats

“…Since the side effects of selective PDE4 inhibitors limit their clinical use, compounds with dual PDE3–PDE4 inhibitory effects will provide a new approach for the development of PDE inhibitors . In our previous study, we identified two compounds, methyl 2‐(2‐fluorobenzamido)benzoate (DSM‐RX78) and ethyl 2‐(2‐fluorobenzamido)benzoate (EFB‐1) (Figure ), which potently inhibited O 2 − generation induced by formyl‐ l ‐methionyl‐ l ‐leucyl‐ l ‐phenylalanine (FMLP) in human neutrophils by inhibiting PDEs . Of these, EFB‐1 dually inhibited the enzymes of PDE4 and PDE3 with IC 50 values (concentration that reduces cell viability by 50%) of 3.61 and 23.3 μ m , respectively .…”

“…[10] In our previous study, we identified two compounds, methyl 2-(2-fluorobenzamido)benzoate (DSM-RX78) and ethyl 2-(2-fluorobenzamido)benzoate (EFB-1) (Figure 1), which potently inhibited O2generation induced by formyl-l-methionyl-l-leucyl-l-phenylalanine (FMLP) in human neutrophils by inhibiting PDEs. [1,11,12] Of these, EFB-1 dually inhibited the enzymes of PDE4 and PDE3 with IC50 values (concentration that reduces cell viability by 50%) of 3.61 and 23.3 mm, respectively. [1] DSM-RX78, an analogue of EFB-1, was also able to elevate cAMP levels by a similar pathway.…”

“…[11] Furthermore, both DSM-RX78 and EFB-1 (each 1.0 mg/kg) were able to attenuate haemorrhagic shock-induced lung injury in rats. [1,11,12] Therefore, DSM-RX78 and EFB-1 could be approved as lead compounds for the development of new drugs to control haemorrhagic shock-induced organ dysfunction.…”