SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins

Abstract

Fatty acid binding proteins (FABPs) serve as critical modulators of endocannabinoid signaling by facilitating the intracellular transport of anandamide and whose inhibition potentiates anandamide signaling. Our previous work has identified a novel small-molecule FABP inhibitor, α-truxillic acid 1-naphthyl monoester (SB-FI-26, 3) that has shown efficacy as an antinociceptive and anti-inflammatory agent in rodent models. In the present work, we have performed an extensive SAR study on a series of 3-analogs as novel FABP inhibitors based on computer-aided inhibitor drug design and docking analysis, chemical synthesis and biological evaluations. The prediction of binding affinity of these analogs to target FABP3, 5 and 7 isoforms was performed using the AutoDock 4.2 program, using the recently determined co-crystal structures of 3 with FABP5 and FABP7. The compounds with high docking scores were synthesized and evaluated for their activities using a fluorescence displacement assay against FABP3, 5 and 7. During lead optimization, compound 3l emerged as a promising compound with the Ki value of 0.21 μM for FABP 5, 4-fold more potent than 3 (Ki, 0.81 μM). Nine compounds exhibit similar or better binding affinity than 3, including compounds 4b (Ki, 0.55 μM) and 4e (Ki, 0.68 μM). Twelve compounds are selective for FABP5 and 7 with >10 μM Ki values for FABP3, indicating a safe profile to avoid potential cardiotoxicity concerns. Compounds 4f, 4j and 4k showed excellent selectivity for FABP5 and would serve as other new lead compounds. Compound 3a possessed high affinity and high selectivity for FABP7. Compounds with moderate to high affinity for FABP5 displayed antinociceptive effects in mice while compounds with low FABP5 affinity lacked in vivo efficacy. In vivo pain model studies in mice revealed that exceeding hydrophobicity significantly affects the efficacy. Thus, among the compounds with high affinity to FABP5 in vitro, the compounds with moderate hydrophobicity were identified as promising new lead compounds for the next round of optimization, including compounds 4b and 4j. For select cases, computational analysis of the observed SAR, especially the selectivity of new inhibitors to particular FABP isoforms, by comparing docking poses, interaction map, and docking energy scores has provided useful insights.

Docetaxel/cabazitaxel and fatty acid binding protein 5 inhibitors produce synergistic inhibition of prostate cancer growth

“…SBFI‐102/SBFI‐103 structures and in vitro affinities (K i , µM), and docetaxel/cabazitaxel structures. The chemical structures and K i values of (A) SBFI‐102 and (B) SBFI‐103 are shown and taken from Yan et al The chemical structures for (C) docetaxel and (D) cabazitaxel. SBFI, Stony Brook fatty acid‐binding protein inhibitor…”

“…17 These second-generation molecules were chosen as candidate inhibitors because they display greater potency than SBFI-26 (in the case of SBFI-102) or greater selectivity against related FABPs (in the case of SBFI-103). 17 We first determined whether our second-generation FABP5 inhibitors produce cytotoxicity in PCa cells. The cytotoxic effects of SBFI-102 ( Figure 2A) and SBFI-103 ( Figure 2B) were assessed in human-derived PC3, DU-145, and 22Rv1 cells that express FABP5.…”

“…Our group has previously developed FABP5 inhibitors based upon the truxillic acid monoester scaffold, including the first‐generation inhibitor Stony Brook fatty acid‐binding protein inhibitor 26 (SBFI‐26) . Our recent efforts have led to the identification of second‐generation FABP5 inhibitors that show enhanced potency or selectivity for FABP5 . Recent work by the Ke group has shown that SBFI‐26 suppresses PCa cell growth, migration, invasion, tumor formation, and metastasis in vitro and in vivo, suggesting that FABP5 inhibitors may constitute efficacious antitumor agents.…”

“…15,16 Our recent efforts have led to the identification of secondgeneration FABP5 inhibitors that show enhanced potency or selectivity for FABP5. 17 Recent work by the Ke group has shown that SBFI-26 suppresses PCa cell growth, migration, invasion, tumor formation, and metastasis in vitro and in vivo, 18 suggesting that FABP5 inhibitors may constitute efficacious antitumor agents. Therefore, the first goal of this work was to determine whether our second-generation FABP5 inhibitors produce cytotoxicity in PCa cells in vitro and reduce tumor growth in vivo.…”

“…20,24 Therefore, F I G U R E 1 SBFI-102/SBFI-103 structures and in vitro affinities (K i , µM), and docetaxel/cabazitaxel structures. The chemical structures and K i values of (A) SBFI-102 and (B) SBFI-103 are shown and taken from Yan et al 17 The chemical structures for (C) docetaxel and (D) cabazitaxel. SBFI, Stony Brook fatty acid-binding protein inhibitor combination therapies consisting of docetaxel/cabazitaxel and other chemotherapeutic agents could lead to enhanced antitumor efficacy or permit the use of lower taxane doses in patients, thus reducing taxane-resistance as well as potentially decreasing the adverse effects associated with taxane chemotherapeutics.…”