We have studied the effects of endogenous and exogenous estrogen on atherosclerotic lesions in apolipoprotein E-deficient mice. Female mice ovariectomized (OVX) at weaning displayed increases (P < 0.01) in fatty streak lesions in the proximal aorta and aortic sinus compared with female mice with intact ovarian function. These differences between the OVX and sham controls were apparent in both chow-and "Western-type" diet-fed mice. Moreover, increases in lesion size following OVX occurred without changes in plasma cholesterol. Hormone replacement with subdermal 17-8-estradiol pellets releasing either 6, 14, or 28 jig/day significantly decreased (P < 0.001) atherosclerotic lesion area in both male and OVX female mice. In contrast, neither 17-a-estradiol (28 ,ig/day) or tamoxifen (85 ,ig/day) affected lesion progression in OVX female mice. In the Western diet-fed group, exogenous estradiol markedly reduced plasma cholesterol and triglycerides, whereas, in animals fed the chow diet, exogenous estrogen and tamoxifen treatment only decreased plasma and very low density lipoprotein triglycerides. However, lesion area was only weakly correlated with plasma cholesterol and triglycerides, 0.35 and 0.44 tau values, respectively (P < 0.01). In summary, in the apolipoprotein E-deficient mouse 17-j8-estradiol protects against atherosclerotic lesion formation, and this can only be partially explained through effects on plasma lipoprotein levels. Cardiovascular diseases resulting from atherosclerosis are a leading cause of death in Western societies (1). Epidemiological studies show men and postmenopausal women are at higher risk for such diseases than are premenopausal women, suggesting that estrogen may be cardioprotective (2, 3). This reduction in risk for cardiovascular disease is caused in part by the effects of estrogen on lipoprotein metabolism and shifts of the plasma lipoproteins to a less atherogenic profile (4). Estrogen, particularly when taken orally, lowers plasma low density lipoprotein (LDL) and raises high density lipoprotein (HDL) levels (5, 6). Although these lipoprotein changes occur in premenopausal women and postmenopausal women receiving hormone replacement therapy, in large-scale studies with adjustments for multiple risk factors, only 25-50% of the beneficial effects of estrogen appear to be due to lipoprotein effects (7).The nonlipid effects of estrogen that may contribute to the cardioprotection observed in humans include the following: effects on endothelial metabolism (8, 9), myocardial conductance, hemostatic factors (10, 11), vascular tone and reactivity (12), intimal cell proliferation (13, 14), Lp(a) levels (15), expression of adhesion molecules (16), platelet aggregation (17), LDL oxidation (18, 19), inflammatory cytokine expression (20, 21), and extracellular matrix synthesis. Additionally, estrogen might affect arterial wall calcification (22), the formation of unstable plaque and the generation of occlusive thrombi (4).Detailed systematic evaluation of these parameters in vivo requir...

Abstract-Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr Ϫ/Ϫ ) mice and apolipoprotein E deficient (apoE Ϫ/Ϫ ) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE Ϫ/Ϫ mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE Ϫ/Ϫ mice at all time points tested. Lesion area reduction was also demonstrated in LDLr Ϫ/Ϫ mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1 Key Words: leukotriene B4 Ⅲ atherosclerosis Ⅲ monocyte chemoattractant protein-1 T he pathogenesis of atherosclerosis is a complex process, which involves the recruitment and activation of monocytes in the developing atherosclerotic lesion. 1 It is thought to initiate when circulating monocytes are first attracted to a site of vascular injury through the upregulation of adhesion molecules and chemotactic factors in the lesion. 2,3 Once attached to the vessel wall, monocytes, attracted by a gradient of chemotactic factors, migrate between the endothelial cells into the subendothelial space where they differentiate into macrophages and become lipid-laden foam cells. 2 A growing body of evidence suggests that the recruitment of monocytes is governed by cell-specific chemoattractants. Several molecules have chemotactic activity for monocytes, including N-formylmethionyl peptides exemplified by N-formylmethionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, the arachidonic acid metabolite leukotriene B4 (LTB4), 12-hydroxyeicosatetraenoic acid (12-HETE), and the chemoattractant monocyte chemotactic protein-1 (MCP-1). 4See page 361 and cover MCP-1 is the prototype of the CC chemokine ␤ subfamily and exhibits the most potent chemotactic activity for monocytes. 5 MCP-1 is highly expressed in human atheromatous plaques, 6 and its overexpression contributes to the development of atherosclerosis in mouse models. 7 In hypercholesterolemic mice, a deficiency in either MCP-1 8 or the MCP-1 receptor (CCR2) 9 results in a marked decrease in atheromas and fewer monocytes in vascular lesions. However, at later stages of lesion development in these mice, differences in lesion size relative to wild type become less pronounced. These data suggest that other chemotactic factors are likely compensating for the lack of MCP-1.LTB4, a product of the 5-lipoxygenase pathway of arachidonic acid metabolism, is also a potent chemoattractant and proinflammatory mediator thought to be involved in the pathogenesis of several ...

Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

Glucokinase is a key regulator of glucose homeostasis and small molecule activators of this enzyme represent a promising opportunity for the treatment of Type 2 diabetes. Several glucokinase activators have advanced to clinical studies and demonstrated promising efficacy; however, many of these early candidates also revealed hypoglycemia as a key risk. In an effort to mitigate this hypoglycemia risk while maintaining the promising efficacy of this mechanism, we have investigated a series of substituted 2-methylbenzofurans as ''partial activators'' of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2carboxamide as an early development candidate.

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