Awd 12-281

Kuss, Hildegard; Höfgen, Norbert; Egerland, Ute; Heer, Stefan; Marx, Degenhard; Szelenyi, Istvan; Schupke, Hubert; Gasparic, Antje; Olbrich, Martin; Hempel, Rolf-Dieter; Hartenhauer, Helge; Krone, D.; Berthold, K.; Kronbach, Thomas; Rundfeldt, Chris

doi:10.1358/dof.2002.027.02.651710

Cited by 5 publications

(1 citation statement)

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“…K-34 possesses a 3,5-dichloro-4-pyridyl moiety which is one of the essential structural components for its PDE4 inhibitory activity. The unique structural feature of this compound is that the linker between the pyridine unit and the benzene unit is a ketone, which is different from most of the other PDE4 inhibitors’ linkers, which are amides . Another unique feature is the spiro acetal moiety which is rarely seen in pharmaceutical compounds .…”

Section: Introductionmentioning

confidence: 99%

Process Development of the PDE4 Inhibitor K-34

Yanagisawa

Taga

Atsumi

et al. 2011

Org. Process Res. Dev.

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A short and practical synthesis of the PDE4 inhibitor K-34 (1) was developed. This synthesis was achieved in four steps and with a 58% overall yield. The unique spiro acetal was created with exceptionally high yield by utilizing the neighbor carboxylic acid assistance. This synthesis also features efficient ketone construction with 4-pyridinylmethyl anion 9 and ester 18, in which overreaction should be prohibited by quick in situ enolate formation. The overall synthesis was carried out under mild conditions and used a simple procedure suitable for large-scale production.

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Section: Introductionmentioning

confidence: 99%

Process Development of the PDE4 Inhibitor K-34

Yanagisawa

Taga

Atsumi

et al. 2011

Org. Process Res. Dev.

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In Vivo Efficacy in Airway Disease Models ofN-(3,5-Dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), a Selective Phosphodiesterase 4 Inhibitor for Inhaled Administration

Kuss¹,

Hoefgen²,

Johanssen³

et al. 2003

J Pharmacol Exp Ther

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- [1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281) is a highly potent and selective phosphodiesterase 4 (PDE4) inhibitor that was designed to have a metabolic profile that was optimized for topical administration. The aim of the current study was to explore the pharmacological profile of intratracheally administered AWD 12-281 in different models of asthma and chronic obstructive pulmonary disease (COPD) in comparison with steroids. To assess the anti-inflammatory potential of AWD 12-281, the antigen-induced cell infiltration in bronchoalveolar lavage fluid (BALF) of Brown Norway rats was determined. AWD 12-281 (ID 50 of 7 g/kg i.t.) as well as beclomethasone (0.1 g/kg i.t.) suppresses late-phase eosinophilia when administered intrapulmonary. Furthermore, AWD 12-281 has also strong anti-inflammatory properties when tested in lipopolysaccharide-induced acute lung neutrophilia in Lewis rats (ID 50 of 0.02 g/kg i.t.), ferrets (ID 50 of 10 g/kg i.t.), and domestic pigs (2-4 mg/pig i.t. or 1 mg/kg i.v.). In pigs, AWD 12-281 was as effective as beclomethasone (0.4 mg/pig i.t.) and dexamethasone (0.28 mg/kg i.v.), although at 3 to 10 times the dosage. The bronchodilatory activity of AWD 12-281 was assessed in sensitized guinea pigs. AWD 12-281 (1.5 mg/kg i.t., 1-h pretreatment) inhibited allergen-induced bronchoconstriction by 68% (parameter airway resistance). In sensitized BP-2 mice AWD 12-281 abolished the allergen-induced bronchial hyperresponsiveness and eosinophilia in BALF, showing dose dependence. When given orally, i.v. or i.t., AWD 12-281 has a considerably lower emetic potential than cilomilast in ferrets and roflumilast in pigs. When given topically by inhalation, no emesis could be induced in dogs up to the highest feasible dose (15 mg/kg in 50% lactose blend). These results indicate that AWD 12-281 is a unique potential new drug for the topical treatment of asthma and COPD.

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Anti-Inflammatory Potential of the Selective Phosphodiesterase 4 InhibitorN-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), in Human Cell Preparations

Draheim¹,

Egerland²,

Rundfeldt³

2003

J Pharmacol Exp Ther

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AWD 12-281 is a potent (IC 50 ϭ 9.7 nM) and highly selective inhibitor of the phosphodiesterase 4 (PDE4) isoenzyme with low affinity to the high-affinity rolipram-binding site. The compound was optimized for topical treatment of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. The aim of the present study was to assess the effect of AWD 12-281 in human inflammatory cells. Peripheral blood mononuclear cells (PBMCs), diluted whole blood, and human nasal polyp cells derived from surgically resected nasal polyps from patients with polyposis comprise sources of target tissue cells that can be used to predict anti-inflammatory effects in patients. AWD 12-281 was capable of suppressing the production of cytokines in stimulated PBMCs: interleukin-2 (IL-2, phytohemagglutinin stimulation), IL-5 (concanavalin A stimulation), IL-5 and IL-4 (anti-CD3/anti-CD28 costimulation), and lipopolysaccharide-stimulated release of tumor necrosis factor ␣ (TNF␣). The corresponding values for halfmaximum inhibition, EC 50 , for AWD 12-281 were within a narrow range (46 -121 nM). Comparing the effect of AWD 12-281 with roflumilast, cilomilast (SB 207499), rolipram (RPR-73401), and 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (RS-25344-000), it could be shown that the PDE4 inhibitory activity was closely correlated with inhibitory potential as measured by the above-described assays. AWD 12-281 was also shown to suppress TNF␣ release in dispersed nasal polyps (EC 50 ϭ 111 nM) and in diluted whole blood (EC 50 ϭ 934 nM). The reduced activity in human blood may be related to high plasma protein binding. Currently, phase II clinical studies are under way to evaluate the therapeutic potential of AWD 12-281 in asthma, COPD, and allergic rhinitis.

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Awd 12-281

Cited by 5 publications

References 0 publications

Process Development of the PDE4 Inhibitor K-34

Process Development of the PDE4 Inhibitor K-34

In Vivo Efficacy in Airway Disease Models ofN-(3,5-Dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), a Selective Phosphodiesterase 4 Inhibitor for Inhaled Administration

Anti-Inflammatory Potential of the Selective Phosphodiesterase 4 InhibitorN-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic Acid Amide (AWD 12-281), in Human Cell Preparations

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