LASSBio‐1829 Hydrochloride: Development of a New Orally Active N‐Acylhydrazone IKK2 Inhibitor with Anti‐inflammatory Properties

Abstract

Inhibitor of nuclear factor κB kinase 2 (IKK2) is suggested to be a potential target for the development of novel anti-inflammatory and anticancer drugs. In this work, we applied structure-based drug design to improve the potency of the inhibitor (E)-N'-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524, 1 a: IC50 =20 μm). The molecular model built for IKK2 together with the docking methodology employed were able to provide important and consistent information with respect to the structural and chemical inhibitor characteristics that may confer potency to IKK2 inhibitors, providing important guidelines for the development of a new N-acylhydrazone (NAH) derivative. (E)-N'-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzylidene)-2-naphthohydrazide hydrochloride (LASSBio-1829 hydrochloride, 10) is a 7-azaindole NAH able to inhibit IKK2 with an IC50 value of 3.8 μm. LASSBio-1829 hydrochloride was found to be active in several pharmacological inflammation tests in vivo, showing its potential as an anti-inflammatory prototype.

Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

“…All N ‐acylhydrazone derivatives ( 3a–d ) were obtained as a single diastereomer. 1 H‐NMR spectra of the compounds did not show any duplication in the amide and imine hydrogens of N ‐acylhydrazone subunit (Table ), that is a strong indication of the presence of the thermodynamically more stable ( E )‐diastereomer, as previously reported by our research group …”

“…Commercially available 2‐naphthoyl chloride ( 4 ) was used as the starting material. To avoid dimerization during the synthesis of hydrazide ( 6 ), acyl chloride ( 4 ) was previously converted in the respective methyl ester ( 5 ) after treatment with methanol at room temperature . Next, methyl 2‐naphthoate ( 5 ) was converted in the respective 2‐naphthohydrazide ( 6 ) through the nucleophilic substitution at the carbonyl group with hydrazine hydrate in ethanol at reflux .…”

“…Synthetic methodologies used to prepare methyl 2‐naphthoate ( 5 ) and 2‐naphthohydrazide ( 6 ) have been carefully described in a previously published work …”

“…LASSBio‐1524 ( 1 , Figure ) was described in 2011 as the first selective IKK‐2 inhibitor presenting the privileged N ‐acylhydrazone structure . In addition, the structure‐based drug optimization of 1 leads us to identify LASSBio‐1829 ( 2 , Figure ) as a potent IKK‐2 inhibitor with oral anti‐inflammatory activity in animal models . A second generation of structurally related N ‐acylhydrazone derivatives LASSBio‐1827 ( 3a ), LASSBio‐1824 ( 3b ), LASSBio‐1832 ( 3c ), and LASSBio‐1823 ( 3d ) (Figure ), designed by molecular simplification and ring isosterism, was also planned as IKK‐2 inhibitors.…”

Discovery of Novel Orally Active Tetrahydro-Naphthyl-N-Acylhydrazones with In Vivo Anti-TNF-α Effect and Remarkable Anti-Inflammatory Properties

“…2'-7'diclorodihidrofluoescein diacetate (DCF-DA, 2 mM) was added to follow by further incubation for 30 minutes at 37°C. The emitted fluorescence was captured in the FL-1 channel flow cytometer (BD Accuri™) and was expressed as DCF-DA fluorescence [ 38 ].…”