title: Biochemical and pharmacological characterization of 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), a novel, orally active elastase inhibitor.
abstract: 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 (K(i)) and the constant for inactivation process (k(on)) being 0.0168 +/- 0.0014 nM and 0.183 +/- 0.013 10(6)/mol sr, respectively. The dissociation rate constant, k(off), was 3.11 + 0.37 10(-6)/s. SSR69071 displays a higher affinity for human elastase than for rat (K(i) = 3 nM), mouse (K(i) = 1.8 nM), and rabbit (K(i) = 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 ED(50) = 10.5 mg/kg p.o. SSR69071 decreases significantly the acute lung hemorrhage induced by HLE (ED(50) = 2.8 mg/kg p.o.) in mice. Furthermore, SSR69071 prevents carrageenan- (ED(30) = 2.2 mg/kg) and HLE-induced (ED(30) = 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.
authors.affiliation: Discovery Research, Sanofi-Synthelabo Internal Medicine Budapest Site, Chinoin, Sanofi-Synthelabo Group, Budapest, Hungary. zoltan.kapui@sanofi-synthelabo.com
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kapui
authors.forename: Marton
authors.initials: M
authors.lastname: Varga
authors.forename: Katalin
authors.initials: K
authors.lastname: Urban-Szabo
authors.forename: Endre
authors.initials: E
authors.lastname: Mikus
authors.forename: Tibor
authors.initials: T
authors.lastname: Szabo
authors.forename: Judit
authors.initials: J
authors.lastname: Szeredi
authors.forename: Sandor
authors.initials: S
authors.lastname: Batori
authors.forename: Olivier
authors.initials: O
authors.lastname: Finance
authors.forename: Peter
authors.initials: P
authors.lastname: Aranyi
mesh_terms: D000465:Algorithms; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002351:Carrageenan; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C474251:SSR 69071; D013844:Thiazoles; D002351:Carrageenan; D004549:Elastin; D019272:Leukocyte Elastase; C108686:ZD 8321