Small molecular anti-cytokine agents

Abstract

The recent successful introduction of the anti-cytokine biologicals Etanercept, Infliximab, Adalimumab, and Anakinra has stimulated the search for anti-cytokine small-molecules. A number of molecular targets have been identified for the development of such small molecular anti-cytokine agents. The focus of this review will be on those inhibitors of cytokine production, which target either p38 mitogen activated protein (MAP) kinase, TNF-alpha converting enzyme (TACE), or IL-1beta converting enzyme (ICE). P38 MAP kinase occupies a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like interleukin 1beta (IL-1beta) and TNF-alpha, and regulates their biosynthesis at both the transcriptional and translational level. TACE and ICE are two proteases required for the processing of proTNF-alpha and proIL-1beta, respectively into their mature, proinflammatory form. Since the mid-1990s, a plethora of inhibitors of p38 MAP kinase, TACE, and ICE has been characterized in vitro, and individual representatives from all three inhibitor classes have in the meantime been advanced into clinical trials. This review will highlight the correlation between effective inhibition at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta, production. Structure-activity relationships (SAR) will be discussed regarding activity at the respective enzyme target, but also with regard to properties required for efficient in vitro and in vivo cellular activity (e.g., oral availability, solubility, cell penetration, etc.).

Synthesis and Selected Reactions of Hydrazides Containing an Imidazole Moiety

“…was neutralized with AcOH and the formed precipitate was filtered off and crystallized from MeOH. 3, [20] using MoK α radiation (λ = 0.71073 Å) from a micro-focus X-ray source and an Oxford Instruments Cryojet XL cooler. Data reduction was performed with CrysAlisPro [20].…”

“…-In a series of our recent publications, various syntheses of imidazole derivatives including optically active products were reported [1]. It is well documented that some imidazole derivatives such as imidazole N-oxides [2], imidazole-2-thiones [3] or 2-sulfanylimidazoles [4] show diverse biological activities. On the other hand, imidazole N-oxides were used for the preparation of more complex N-heterocles via Pd-catalyzed direct arylation [5], and in the case of optically active derivatives, they were applied as promising ligands for asymmetric allylation of aromatic aldehydes [6].…”

Identification and Characterization of a Novel Class of c-Jun N-terminal Kinase Inhibitors

“…JNKs are directly involved in controlling regulation of AP-1 transcriptional activity; therefore, drug discovery efforts have focused on the development of JNK inhibitors for treatment of chronic inflammatory diseases (Bennett et al, 2003;Wagner and Laufer, 2006;Jung et al, 2010). One of the targets of activated JNKs is c-Jun, which is specifically phosphorylated on Ser63 and/or Ser73, making this protein capable of binding AP-1 sites in the nucleus (Hibi et al, 1993).…”

Synthesis and Biological Testing of N‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors

“…[8] Various well-known ATP-competitive MAPK inhibitors have since been developed which are derived from the prototype inhibitors SK&F 86002 and SB 203580 (Figure 1). [10][11][12] Various potent and selective p38a inhibitors are currently in phase II clinical studies for rheumatoid arthritis, psoriasis, inflammatory bowel diseases, neuropathic pain, cancer, depression, and cardiovascular diseases. [13] With respect to the pyridinylimidazoles, it was revealed that 2-sulfanylimidazoles offer advantages over SB 203580, such as fewer cytochrome P450 (CYP450) interactions and improved kinetic properties.…”