Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5-Lipoxygenase Activating Protein Inhibitors: Discovery of 2-[4-(3-{(R)-1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915)

Abstract

The synthesis, structure-activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC50 < 10 nM) and potent inhibition of LTB4 synthesis in human whole blood (IC50 < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.

Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening

“…In 2015 research on FLAP inhibitors received another boost with the development of a series of oxadiaozole-containing FLAP inhibitors, shown by Takahashi et al . 16 and the discovery of AZD6642, another potent FLAP inhibitor 17 .…”

Recent development of lipoxygenase inhibitors as anti-inflammatory agents

“…17) was designed and synthesized, and evaluated as a novel FLAP inhibitor at Boehringer Ingelheim Pharmaceuticals. 86 The IC 50 values for FLAP binding and human whole blood LTB 4 production were 1.7 nM and 45 nM, re-spectively, and the aqueous equilibrium solubility at pH 6.8 was 48 μg mL −1 . Additionally, in terms of potential drug-drug interactions, BI-665915 was predicted to have a low risk.…”

Donated chemical probes for open science

“…Many quality probe compounds are buried in the chemical vaults of the pharmaceutical industry, depriving the scientific community of useful tools and limiting the impact of the original research. In some cases, particular compounds, their properties and some structure–activity relationships (SAR) have been published ( Nara et al, 2014 ; Siebeneicher et al, 2016 ; Takahashi et al, 2015 ; Wu-Wong et al, 1999 ). However, often only selected data are published and the proprietary compounds are not made available to the researchers except via restrictive contractual agreements, and this impedes their use and their impact.…”