Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 3: Orally active anti-inflammatory agents

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Abstract

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IκB kinase β (IKK-β) inhibitors. Modification of a novel IKK-β inhibitor 1 (IKK-β IC50 = 1500 nM, Cell IC50 = 8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-β IC50 = 8.5 nM, Cell IC50 = 60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1 mg/kg, po in arachidonic acid-induced ear edema model in mice).

Introduction

IκB kinase β (IKK-β) is a 756 amino acid-containing serine-threonine protein kinase.1 As part of the IKK-complex, IKK-β is critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-κB) in response to various inflammatory stimuli.2 NF-κB is an inducible transcription factor that is thought to be a pivotal target for drugs for cancer and chronic inflammatory diseases. Herein, we report the synthesis and the structure–activity relationship (SAR) study of a novel class of small molecule IKK-β inhibitors.

In the preceding communications,[3], [4] we described the SAR study of a novel IKK-β inhibitor 1 identified via screening of the Bayer compound library (Fig. 1). First we found that various functional groups were tolerated on the 4-phenyl ring without losing activity.3 Moreover, replacing the substituted phenyl ring at the 4-position of the pyridine ring with an aliphatic group incorporating a primary amine resulted in a marked increase of the IKK-β inhibitory activity, albeit with no improvement in the cellular activity (TNFα-induced RANTES production in A549 cells), as exemplified by compound 2 derived from a phenylalanine derivative.4 In order to improve the cellular activity, the 4-aminoalkyl group was further optimized, and 4-piperidin-3-ylpyridine analog 3a was identified as a potent IKK-β inhibitor with excellent cellular activities.4 However, the bioavailability of compound 3a in mice and rats was less than satisfactory. Thus, we continued the modification of compound 3a to discover highly potent and orally active IKK-β inhibitors with anti-inflammatory effect.

Section snippets

Chemistry5

The 2-amino-6-aryl-3-cyano-4-piperidinylpyridine core structures can be easily constructed using a one-pot coupling reaction of four components, acetophenone, N-Boc-formylpiperidine, malononitrile and ammonium acetate, as exemplified in Scheme 1, Scheme 2.

Results and discussion

In our initial SAR study, the in vitro activity was improved readily by the modification of the substituent at the 4-position on the pyridine core ring. In order to identify more potent and orally active IKK-β inhibitors, our synthetic strategy was next shifted to optimization of the ortho-phenol group of the compound 3a, which would be readily implemented using commercially available substituted 2′-hydroxyacetophenone derivatives by the usual synthetic procedure. In addition, since the initial

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