Richard F. Bousley

CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys

Lipoprotein(a) (Lp(a)), which is generated through the covalent association of apolipoprotein(a) (apo(a)) and apo B-100-LDL, is an independent risk factor for several vascular diseases. Therefore, there is interest in developing therapies for lowering Lp(a). This investigation was carried out to determine the effect of CI-1011, a potent lipid regulator in rodents, on Lp(a) and other lipid parameters in cynomolgus monkeys (Macaca fascicularis). Nine healthy male monkeys on a normal chow diet were orally treated with CI-1011 at 30 mg/kg per day for 3 weeks. Lp(a) and total cholesterol levels were significantly decreased after 1 week and maximally reduced to 68 and 73% of control levels, respectively, after 3 treatment weeks. The decreases in total cholesterol were mainly due to changes in low density lipoprotein (LDL). The LDL:HDL ratio decreased by 30%. Triglycerides were unaffected by treatment. Lp(a) and total cholesterol levels returned to pretreatment values after stopping treatment suggesting a direct effect of the compound on their inhibition. Further studies demonstrated that CI-1011 was effective at a low dose of 3 mg/kg per day after 1 week of administration. CI-1011 also decreased apo B-100 to 80% of control levels, but this change was not sufficient to account for the Lp(a) lowering. There was also no correlation between the changes in Lp(a) and apo B-100 levels. Treatment of cynomolgus monkey primary hepatocyte cultures with CI-1011 resulted in a dose-dependent inhibition of Lp(a) levels suggesting a direct hepatic effect of the compound. Western blot analysis of the samples showed that changes in Lp(a) were associated mainly with decreased apo(a) (47%), but not apo B-100 (17%). These results demonstrate that CI-1011 effectively decreases Lp(a) levels both in vivo and in vitro.

Inhibitors of Acyl-CoA:Cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: Synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates

Sulfoacetic acid, phosphoramidate, and phosphoramide analogs of the ACAT inhibitors, CI-999 and CI-1011 were synthesized. The structure-activity relationships of these compounds as ACAT inhibitors are described.

Opposite effects of bezafibrate and gemfibrozil in both normal and hypertriglyceridemic rats

Chow and sucrose-fed rats were used as animal models to study the dose-responses of bezafibrate and gemfibrozil in normolipidemic and hypertriglyceridemic states, respectively. Although both drugs lowered plasma triglycerides (TG) to about the same extent in chow-fed rats, gemfibrozil lowered liver TG as well as plasma total and LDL-cholesterol (LDL-C), but elevated HDL-cholesterol (HDL-C) and plasma apo E concentrations. Bezafibrate produced opposite effects, namely, decreased HDL-C, apo E and liver TG, and tended to increase LDL-C. TG lowering for both drugs in chow-fed rats was not due to changes in TG secretion (production) in normal rats but was associated with enhanced LPL activity. In hypertriglyceridemic rats both drugs modestly reduced TG secretion rates about 40% at a dose producing maximal TG lowering, but again, gemfibrozil elevated and bezafibrate lowered HDL-C and apo E. Unlike gemfibrozil, bezafibrate induced the appearance of LDL-C in hypertriglyceridemic rats which was not detected in control animals, and also tended to increase rather than decrease plasma apo B levels. Finally, changes in liver TG concentration (mg/g) in hypertriglyceridemic rats were opposite for these drugs, resulting in significant drug-related differences in liver TG content (mg/organ). From these data we postulate that, although similar with regard to TG lowering activity and mechanisms thereof, gemfibrozil and bezafibrate produce fundamentally different effects on LDL, HDL and apolipoprotein metabolism (apo B and apo E) in rats which may relate to potential differential effects on reverse cholesterol transport and atherogenesis.

Inhibitors of acyl-CoA: Cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 13. Design, synthesis and biological evaluation of tetrazole anilides as potent inhibitors of ACAT in vitro and hypocholesterolemic agents in vivo

Abstract The syntheses and biological activities for anilides derived from 2-phenyl-2-(dodecyl-2H-tetrazol-5-yl)acetic acid are described. Evidence is provided that one of these compounds, (+)- 8b , stereoselectively inhibits ACAT in vitro and possesses superior efficacy in vivo compared to (−)- 8b or the recemic mixture (±)- 8b .

Inhibitors of acyl-coa:cholesterol acyltransferase (ACAT). 15. sulfonylurea inhibitors with excellent hypocholesterolemic activity in vivo.

Abstract A series of sulfonylureas were prepared and tested for the ability to inhibit the enzyme acyl-CoA: cholesterol acyltransferase (ACAT) in vitro and lower plasma cholesterol in cholesterol-fed rats in vivo. Although compounds from this series were generally weak inhibitors of ACAT in vitro, several displayed excellent hypocholesterolemic activity in vivo.

Antithrombotic effect of LB-30057 (CI-1028), a new synthetic thrombin inhibitor, in a rabbit model of thrombosis: Comparison with inogatran

LB-30057 (CI-1028) is a novel, orally bioavailable, direct thrombin inhibitor with a Ki of 0.38[emsp4 ]nM against human thrombin. The effects of LB-30057 on thrombus formation and hemostasis were evaluated in a veno-venous shunt model of thrombosis in rabbits, and compared with inogatran, another direct inhibitor of thrombin. Each compound was studied at 5 or 6 different doses with 5 or 6 rabbits in each group. After administration as a bolus i.v. injection followed by continuous infusion, both LB-30057 and inogatran dose-dependently inhibited thrombus formation, which was measured as an increase in time to occlusion (TTO) and a decrease in thrombus weight. Both compounds also improved vena caval blood flow and reduced the overall incidence of thrombotic occlusion. LB-30057 significantly prolonged TTO from 23±4[emsp4 ]min (before dose) to 110±10[emsp4 ]min at the highest dose (0.7[emsp4 ]mg/kg+47[emsp4 ]μg/kg/min) (p<0.001), and reduced thrombus weight from 57±2[emsp4 ]mg to 15±5[emsp4 ]mg (p<0.001). Occlusive thrombus formed in only one of six rabbits that received the highest dose of LB-30057 (vs. 13/13 in the control group, p<0.01). At the dose that produced the maximum antithrombotic effect (0.7[emsp4 ]mg/kg+47[emsp4 ]μg/kg/min), LB-30057 increased aPTT and bleeding time approximately 2-and 2.5-fold above baseline, respectively. On a gravimetric basis, LB-30057 and inogatran displayed comparable in vivo antithrombotic efficacy. When compared to equally effective anti thrombotic doses of inogatran, LB-30057 caused less prolongation in aPTT, had no effect on PT, and tended to have less of effect on bleeding time. These results indicate that LB-30057 is an effective antithrombotic compound and it appears to have a better benefit/risk profile than inogatran in this experimental model.

Inhibitors of acyl-CoA: Cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 12. Syntheses and biological activity of structurally novel tetrazole amides

Abstract The identification of tetrazole benzamide and nicotinamide derivatives as new structural classes of potent ACAT inhibitors is described. The ensuing structure-activity relationship (SAR) studies revealed that retroamide 8c and 7q possesses comparable in vitro potency and efficacy to that of the fatty acid anilide, CI-976 ( 1 ).

Inhibitors of Acyl-CoA:Cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents 14. synthesis and structure-activity relationships of a novel series of sulfonamide tetrazoles

Abstract The syntheses and biological activities of a series of novel sulfonamide tetrazole derivatives are reported. The ability of these compounds to inhibit ACAT is described. Such agents may decrease the absorption of dietary cholesterol in the intestine and/or the secretion of VLDL by the liver and therefore provide a therapy for the treatment of hypercholesterolemia and atherosclerosis in man.