Structural Optimization and Biological Evaluation of 2-Substituted 5-Hydroxyindole-3-carboxylates as Potent Inhibitors of Human 5-Lipoxygenase

Abstract

Pharmacological suppression of leukotriene biosynthesis by inhibitors of 5-lipoxygenase (5-LO) is a strategy to intervene with inflammatory and allergic disorders. We recently presented 2-amino-5-hydroxy-1H-indoles as efficient 5-LO inhibitors in cell-based and cell-free assays. Structural optimization led to novel benzo[g]indole-3-carboxylates exemplified by ethyl 2-(3-chlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (compound 11a), which inhibits 5-LO activity in human neutrophils and recombinant human 5-LO with IC(50) values of 0.23 and 0.086 microM, respectively. Notably, 11a efficiently blocks 5-LO product formation in human whole blood assays (IC(50) = 0.83-1.6 microM) and significantly prevented leukotriene B(4) production in pleural exudates of carrageenan-treated rats, associated with reduced severity of pleurisy. Together, on the basis of their high potency against 5-LO and the marked efficacy in biological systems, these novel and straightforward benzo[g]indole-3-carboxylates may have potential as anti-inflammatory therapeutics.

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…Note that these compounds also repressed anti-inflammatory properties and significantly reduced LTB 4 and PGE 2 levels (but not 6-keto PGF 1α ) in vivo (mouse paw edema and rat pleurisy) [104,105] (Table 2). Importantly, 5-LO product synthesis in intact neutrophils or human whole blood as well as PGE 2 generation in A549 cells was efficiently repressed by cmpd.…”

“…Relevant disease models are therefore in need to obtain insights into the efficacy and safety of mPGES-1 inhibitors, among others assisted by targeted lipidomics in combination with system biologybased in silica network models. Tables Table 1 Synthetic and natural product M a n u s c r i p t 54 [104,105] …”

Structure and Ligand Based Drug Design Strategies in the Development of Novel 5- LOX Inhibitors

“…Forty compounds with IC 50 values ranging from 0.031 to 13.4 µM for 5-LOX were selected from the literature [106]. The IC 50 values were converted into corresponding pIC 50 values by the formula in Eq.…”

Identification and Development of Mpges-1 Inhibitors: Where We are At?

“…In efforts to develop dual mPGES-1/5-LOX inhibitors, indole-3-carboxylates were screened for their ability to inhibit mPGES-1, as they have previously been shown to potently suppress LTs production by inhibiting 5-LOX [105]. Structural optimization led to the identification of benzo[g] indol-3-carboxylates as mPGES-1 inhibitors exemplified by 42 ( Table 6).…”