TY - JOUR T1 - Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4<em>H</em>-pyrido[1,2-<em>a</em>]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2<em>H</em>)-one-1,1-dioxide (<a href="pending:yes" l:ref-type="genpept" l:ref="SSR69071">SSR69071</a>), a Novel, Orally Active Elastase Inhibitor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 451 LP - 459 DO - 10.1124/jpet.102.044263 VL - 305 IS - 2 AU - Zoltán Kapui AU - Márton Varga AU - Katalin Urban-Szabó AU - Endre Mikus AU - Tibor Szabó AU - Judit Szeredi AU - Sándor Bátori AU - Olivier Finance AU - Péter Arányi Y1 - 2003/05/01 UR - http://jpet.aspetjournals.org/content/305/2/451.abstract N2 - Human leukocyte elastase (HLE) is a proteinase capable of degrading a variety of proteins. Under normal circumstances, the proteolytic activity of HLE is effectively controlled by its natural inhibitors. However, an imbalance between elastase and its endogenous inhibitors may result in several pathophysiological states such as chronic obstructive pulmonary disease, asthma, emphysema, cystic fibrosis, and chronic inflammatory diseases. It is anticipated that an orally active HLE inhibitor could be useful for the treatment of these diseases. 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071) is a potent inhibitor of HLE, with the inhibition constant (Ki) and the constant for inactivation process (kon) being 0.0168 ± 0.0014 nM and 0.183 ± 0.013 106/mol sr, respectively. The dissociation rate constant, koff, was 3.11 + 0.37 10−6/s. SSR69071 displays a higher affinity for human elastase than for rat (Ki = 3 nM), mouse (Ki = 1.8 nM), and rabbit (Ki = 58 nM) elastases. Bronchoalveolar lavage fluid from mice orally treated with SSR69071 inhibits HLE (ex vivo), and in this model, SSR69071 has a dose-dependent efficacy with an ED50 = 10.5 mg/kg p.o. SSR69071 decreases significantly the acute lung hemorrhage induced by HLE (ED50 = 2.8 mg/kg p.o.) in mice. Furthermore, SSR69071 prevents carrageenan- (ED30 = 2.2 mg/kg) and HLE-induced (ED30 = 2.7 mg/kg) paw edema in rats after p.o. administration. In conclusion, SSR69071 is a selective, orally active, and potent inhibitor of HLE with good penetration in respiratory tissues. The American Society for Pharmacology and Experimental Therapeutics ER -