Underwood D C, Bochnowicz S, Osborn R R, Kotzer C J, Luttmann M A, Hay D W, Gorycki P D, Christensen S B, Torphy T J
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
J Pharmacol Exp Ther. 1998 Dec;287(3):988-95.
We evaluated the airway activity of the novel phosphodiesterase type 4 inhibitor SB 207499 [Ariflo; c-4-cyano-4-(3-cyclopentyloxy-4-methoxyp henyl-r-1-cyclohexane carboxylic acid)], in the guinea pig. Ovalbumin (OA)-induced contractions of guinea pig isolated tracheal strips were inhibited by SB 207499 with an EC50 of 1 microM but had little or no effect on exogenous agonist-induced contraction, which suggests that its effect on OA-induced contraction in vitro is primarily due to inhibition of mediator release from mast cells. In anesthetized guinea pigs, SB 207499 inhibited OA-induced bronchoconstriction with i.v. and p.o. ID50 values of 1.7 and 17 mg/kg, respectively. At 1, 3 and 6 hr after SB 207499 (30 mg/kg p.o.), OA-induced bronchospasm was inhibited by 92%, 70% and 58%, respectively, corresponding to elevated plasma concentrations of 1.62 +/- 0.19, 1.65 +/- 0.29 and 0. 93 +/- 0.24 microg/ml, respectively, of SB 207499. SB 207499 also inhibited house dust mite-induced bronchoconstriction (ID50 = 0.9 mg/kg i.v. and 8.9 mg/kg p.o.). In contrast to its lack of bronchorelaxant activity in vitro, SB 207499 inhibited bronchospasm induced by i.v. leukotriene D4 (LTD4) [ID50 = 3 mg/kg i.v.]. The bronchorelaxant effect of i.v.-administered SB 207499 was at least additive with that of salbutamol in reversing infused histamine-enhanced airway tone, but it did not alter base line or enhance salbutamol-induced cardiovascular effects. In conscious guinea pigs, SB 207499 (10 or 30 mg/kg p.o.), 1 hr before antigen or LTD4 challenge, markedly reduced bronchospasm and subsequent eosinophil influx as measured by bronchoalveolar lavage 24 hr after provocation. SB 207499 administered after OA or LTD4 challenge also reduced airway eosinophilia measured at 24 hr after OA challenge or 96 hr after LTD4 challenge. These results, coupled with the broad anti-inflammatory activity of SB 207499 previously described (Barnett et al., 1998), suggest that SB 207499 will be useful in the treatment of asthma and other inflammatory disorders.
我们在豚鼠中评估了新型磷酸二酯酶4型抑制剂SB 207499[阿瑞吡坦；c-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-r-1-环己烷羧酸]的气道活性。SB 207499可抑制卵清蛋白(OA)诱导的豚鼠离体气管条收缩，其半数有效浓度(EC50)为1微摩尔，但对外源性激动剂诱导的收缩作用很小或无作用，这表明其对体外OA诱导收缩的作用主要是由于抑制肥大细胞释放介质。在麻醉的豚鼠中，SB 207499静脉注射和口服的半数抑制剂量(ID50)分别为1.7和17毫克/千克，可抑制OA诱导的支气管收缩。在口服SB 207499(30毫克/千克)后1、3和6小时，OA诱导的支气管痉挛分别被抑制92%、70%和58%，相应的SB 207499血浆浓度分别升高至1.62±0.19、1.65±0.29和0.93±0.24微克/毫升。SB 207499也可抑制屋尘螨诱导的支气管收缩(ID50 = 0.9毫克/千克静脉注射和8.9毫克/千克口服)。与它在体外缺乏支气管舒张活性相反，SB 207499可抑制静脉注射白三烯D4(LTD4)诱导的支气管痉挛[ID50 = 3毫克/千克静脉注射]。静脉注射SB 207499的支气管舒张作用在逆转输注组胺增强的气道张力方面至少与沙丁胺醇有相加作用，但它不改变基线或增强沙丁胺醇诱导的心血管效应。在清醒的豚鼠中，在抗原或LTD4激发前1小时口服SB 207499(10或30毫克/千克)，可显著减轻支气管痉挛以及激发后24小时通过支气管肺泡灌洗测量的随后嗜酸性粒细胞流入。在OA或LTD4激发后给予SB 207499也可减少在OA激发后24小时或LTD4激发后96小时测量的气道嗜酸性粒细胞增多。这些结果，再加上先前描述的SB 207499的广泛抗炎活性( Barnett等人，1998年)，表明SB 207499将有助于治疗哮喘和其他炎症性疾病。
