Kuss H, Hoefgen N, Johanssen S, Kronbach T, Rundfeldt C
Department of Pharmacology, elbion AG, Radebeul, Germany.
J Pharmacol Exp Ther. 2003 Oct;307(1):373-85. doi: 10.1124/jpet.103.053942. Epub 2003 Aug 27.
N-(3,5-Dichloro-pyrid-4-yl)-[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 (ID50 of 7 microg/kg i.t.) as well as beclomethasone (0.1microg/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 (ID50 of 0.02 microg/kg i.t.), ferrets (ID50 of 10 microg/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.
N-(3,5-二氯吡啶-4-基)-[1-(4-氟苄基)-5-羟基吲哚-3-基]-乙醛酸酰胺（AWD 12-281）是一种高效且选择性的磷酸二酯酶4（PDE4）抑制剂，其设计目的是具有针对局部给药进行优化的代谢特征。本研究的目的是探究经气管内给予AWD 12-281在不同哮喘和慢性阻塞性肺疾病（COPD）模型中的药理学特征，并与类固醇进行比较。为评估AWD 12-281的抗炎潜力，测定了棕色挪威大鼠支气管肺泡灌洗液（BALF）中抗原诱导的细胞浸润情况。经肺内给药时，AWD 12-281（气管内注射半数抑制剂量为7微克/千克）以及倍氯米松（气管内注射0.1微克/千克）可抑制迟发性嗜酸性粒细胞增多。此外，在Lewis大鼠（气管内注射半数抑制剂量为0.02微克/千克）、雪貂（气管内注射半数抑制剂量为10微克/千克）和家猪（气管内注射2 - 4毫克/头或静脉注射1毫克/千克）的脂多糖诱导的急性肺中性粒细胞增多模型中进行测试时，AWD 12-281也具有强大的抗炎特性。在家猪中，AWD 12-281与倍氯米松（气管内注射0.4毫克/头）和地塞米松（静脉注射0.28毫克/千克）效果相当，尽管剂量是其3至10倍。在致敏豚鼠中评估了AWD 12-281的支气管舒张活性。AWD 12-281（气管内注射1.5毫克/千克，预处理1小时）可使变应原诱导的支气管收缩抑制68%（参数为气道阻力）。在致敏BP - 2小鼠中，AWD 12-281消除了变应原诱导的支气管高反应性以及BALF中的嗜酸性粒细胞增多，呈剂量依赖性。当经口服、静脉注射或气管内给药时，AWD 12-281在雪貂中的催吐潜力明显低于西洛司特，在家猪中低于罗氟司特。当通过吸入进行局部给药时，在犬中给予最高可行剂量（50%乳糖混合物中15毫克/千克）也不会引起呕吐。这些结果表明，AWD 12-281是一种用于哮喘和COPD局部治疗的独特潜在新药。
