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

作者：Cheng Yih Dih; Hwang Tsong Long; Wang Han Hsiang; Pan Tai Long; Wu Chin Chung; Chang Wen Yi; Liu Yi Ting; Chu Tzu Chi; Hsieh Pei Wen^*

来源：Organic and Biomolecular Chemistry, 2011, 9(20): 7113-7125.

DOI：10.1039/c1ob05714f

Our previous studies identified two 2-benzoylaminobenzoate derivatives 1, which potently inhibited superoxide (O(2)(center dot-)) 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)(center dot-) in human neutrophils with IC(50) values of 0.20, 0.16, 0.15, 0.06, and 0.29 mu M, 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)(center dot-) 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.

• 出版日期2011
• 单位长春大学