N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors

Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity

“…Several other selective FABP4 inhibitors have also been reported with various degrees of in vitro (but not in vivo) characterizations ( 12,17,18 ). In this study, we present the recent report showed that >70% germline knockdown of FABP4 by RNA interference in mice did not improve insulin sensitivity in diet-induced obese mice ( 31 ).…”

“…Indeed, a selective biphenyl azole inhibitor of FABP4, BMS309403, was identifi ed as binding FABP4 with nM affi nity and >100-fold selectivity against FABP5 as well as the heart isoform FABP3 ( 9 ). In a ligand displacement assay using 1,8-ANS (8-anilino-1-naphthalene-sulfonic acid) as the probe, the compound displays inhibition constant ( K i ) values of <2 nM, 250 nM, and 350 nM for FABP4, FABP5, and FABP3, respectively ( 10 ) (12)(13)(14), with one compound displaying an IC 50 value of 600 nM in a fl uorescence polarization (FP) assay ( 15 ), and another compound in the same series an IC 50 value of 49 nM in a scintillation proximity assay ( 16 ). However, no biological characterization in cell-based or in vivo assays has been reported.…”

“…TdF K d (for FABP4 and FABP3) and FP IC 50 values (for FABP4 and FABP5) of our compounds, together with several representative FABP4 inhibitors published in the literature ( 11,12,17 ), are summarized in Table 1 . In both TdF and FP assays, the FABP4 affi nity of our compounds was comparable to that of BMS309403 and Biovitrum 2a, whereas HTS01037 was notably weaker ( Fig.…”

Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice

“…Of a series of chemical inhibitors of FABP4 that was discovered over the last decade [12,[14][15][16][17] , the selective inhibitor BMS309403 was proven to be effective for improving insulin resistance in the ob/ob mouse model and can ameliorate the symptoms of atherosclerosis [7] . However, none of these compounds are in clinical development.…”

“…The binding mode demonstrated that the 3,5-dibromo-4-hydroxyphenyl moiety of BBR is nicely accommodated in a lipophilic pocket defined by Phe16, Tyr19, Met20, Val25, Thr29, Ala33, Phe57, Figure 3A). Moreover, the carbonyl group of BBR forms stable polar interaction with Arg126, a critical residue for the binding of inhibitors [12,[14][15][16][17] . In addition, the oxygen atom in the benzofuran of BBR forms a hydrogen bond with Ser55 ( Figure 3A).…”