Identification of a Potent, Selective, and Orally Active Leukotriene A₄ Hydrolase Inhibitor with Anti-Inflammatory Activity

Abstract

LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.

Concise Synthesis of Broussonone A

“…In order to synthesize the compound 2, we commenced our investigation by employing a Wittig reaction between aldehydes 3 and the corresponding phosphonium salt 5, derived from the commercially available 2-(4-hydroxyphenyl) ethanol [6,7]. However, the Wittig reaction failed to afford our desired product 2 presumably due to low reactivity of the electron-rich benzaldehydes 3 (Scheme 2) [8].…”

Microwave-assisted conversion of aromatic heterocyclic nitriles to various heterocyclic molecules

“…These types of heterocyclic compounds exhibit antitumor (8,9) anti-inflammatory (10,11), antibacterial (12), antiviral (13), and antimicrobial (14) activities. Since this investigation deals with a new approach to synthesize these medicinally important heterocyclic compounds, it is essential to review the procedures reported in literature.…”

Analog based pharmacophore strategy to identify novel leukotriene a4 hydrolase (LTA4H) inhibitors

“…For the pharmacophore modeling studies, a set of LTA4H inhibitory activity data (IC50) spanning over 4 orders of magnitude (from 1 to 630,000 nM) were selected [8][9][10][11][12][13]. The dataset was divided into training set (Insert Fig 1) and test set (supplementary information Table1).…”