Ritchie D M, Kirchner T, Moore J B, Dodd J H, Ahmed T, Anderson D W, Capetola R J
R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869.
Int Arch Allergy Immunol. 1993;100(3):274-82. doi: 10.1159/000236424.
RWJ 22108 (N-benzyl-N-methylaminoethyl 9-(2-chloro-6-fluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1, 1-dioxothiacyclohepteno-[3,2-b]pyridine-8-carboxylate) is a new bronchoselective calcium entry blocker with potential use as an antiasthmatic agent. Previous studies have shown that RWJ 22108 is a potent calcium entry blocker in vitro and demonstrates tissue selectivity for airway smooth muscle over vascular smooth muscle. The current study demonstrates the in vivo activity of RWJ 22108 in several different models of airway obstruction and asthma. RWJ 22108 relaxes preconstricted airways in dogs with little effect on blood pressure when administered by aerosol. In addition, it inhibits airway obstruction induced by antigen, histamine and exogenous leukotriene D4 in guinea pigs. In a conscious sheep model of allergic asthma, aerosol RWJ 22108 inhibits antigen-induced early and late phase airway obstruction and also the cellular infiltration associated with late phase. Total leukotrienes production is decreased in the guinea pig model probably as a result of fewer inflammatory cells infiltrating the lungs as shown in the sheep model of late phase. These data suggest that RWJ 22108 may have pharmacological potential in the clinical management of asthma.
RWJ 22108（N-苄基-N-甲基氨基乙基9-(2-氯-6-氟苯基)-2,3,4,5,6,9-六氢-7-甲基-1,1-二氧代硫杂环庚烯并-[3,2-b]吡啶-8-羧酸酯）是一种新型的支气管选择性钙内流阻滞剂，有作为抗哮喘药物的潜在用途。先前的研究表明，RWJ 22108在体外是一种强效的钙内流阻滞剂，并且对气道平滑肌比对血管平滑肌表现出组织选择性。当前的研究证明了RWJ 22108在几种不同的气道阻塞和哮喘模型中的体内活性。当通过气雾剂给药时，RWJ 22108可使犬预先收缩的气道舒张，而对血压影响很小。此外，它可抑制豚鼠中由抗原、组胺和外源性白三烯D4诱导的气道阻塞。在变应性哮喘的清醒绵羊模型中，气雾剂RWJ 22108可抑制抗原诱导的早期和晚期气道阻塞以及与晚期相关的细胞浸润。在豚鼠模型中，总白三烯生成减少，这可能是由于如在晚期绵羊模型中所示，浸润肺的炎症细胞较少。这些数据表明，RWJ 22108在哮喘的临床管理中可能具有药理学潜力。
