Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats.

This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNFalpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.

SSR182289A, a novel, orally active thrombin inhibitor: in vitro profile and ex vivo anticoagulant activity.

SSR182289A competitively inhibits human thrombin (K(i) = 0.031 +/- 0.002 microM) and shows good selectivity with respect to other human proteases, e.g., trypsin (K(i) = 54 +/- 2 microM), factor Xa (K(i) = 167 +/- 9 microM), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K(i) values >250 microM). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC100 thrombin time 96 +/- 7 nM) and inhibited tissue factor-induced thrombin generation (IC50 of 0.15 +/- 0.02 microM). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC50 value of 32 +/- 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 +/- 356%; ecarin clotting time (ECT), 1134 +/- 204%; and activated partial thromboplastin time (aPTT), 91 +/- 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 +/- 425%; ECT, 2017 +/- 341%; and aPTT, 113 +/- 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.