Dual-action hypoglycemic and hypocholesterolemic agents that inhibit glycogen phosphorylase and lanosterol demethylase

Departments of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
The Journal of Lipid Research (Impact Factor: 4.42). 04/2005; 46(3):547-63. DOI: 10.1194/jlr.M400436-JLR200
Source: PubMed


Diabetic dyslipidemia requires simultaneous treatment with hypoglycemic agents and lipid-modulating drugs. We recently described glycogen phosphorylase inhibitors that reduce glycogenolysis in cells and lower plasma glucose in ob/ob mice (J. Med. Chem., 41: 2934, 1998). In evaluating the series prototype, CP-320626, in dogs, up to 90% reduction in plasma cholesterol was noted after 2 week treatment. Cholesterol reductions were also noted in ob/ob mice and in rats. In HepG2 cells, CP-320626 acutely and dose-dependently inhibited cholesterolgenesis without affecting fatty acid synthesis. Inhibition occurred together with a dose-dependent increase in the cholesterol precursor, lanosterol, suggesting that cholesterolgenesis inhibition was due to lanosterol 14alpha-demethylase (CYP51) inhibition. In ob/ob mice, acute treatment with CP-320626 resulted in a decrease in hepatic cholesterolgenesis with concomitant lanosterol accumulation, further implicating CYP51 inhibition as the mechanism of cholesterol lowering in these animals. CP-320626 and analogs directly inhibited rhCYP51, and this inhibition was highly correlated with HepG2 cell cholesterolgenesis inhibition (R2 = 0.77). These observations indicate that CP-320626 inhibits cholesterolgenesis via direct inhibition of CYP51, and that this is the mechanism whereby CP-320626 lowers plasma cholesterol in experimental animals. Dual-action glycogenolysis and cholesterolgenesis inhibitors therefore have the potential to favorably affect both the hyperglycemia and the dyslipidemia of type 2 diabetes.

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    • "The percent inhibition of triene formation with methanol controls was determined with each inhibitor at three to six concentrations in triplicate and the average was used as described previously (Harwood et al., 2005). The IC 50 was calculated from a graph of percent CYP51 activity remaining versus inhibitor concentration using DeltaGraph (version 4.0; Monterey, CA). "
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    ABSTRACT: CYP51 fulfills an essential requirement for all cells, by catalyzing three sequential mono-oxidations within the cholesterol biosynthesis cascade. Inhibition of fungal CYP51 is used as a therapy for treating fungal infections, whereas inhibition of human CYP51 has been considered as a pharmacological approach to treat dyslipidemia and some forms of cancer. To predict the interaction of inhibitors with the active site of human CYP51, a three-dimensional quantitative structure-activity relationship model was constructed. This pharmacophore model of the common structural features of CYP51 inhibitors was built using the program Catalyst from multiple inhibitors (n = 26) of recombinant human CYP51-mediated lanosterol 14alpha-demethylation. The pharmacophore, which consisted of one hydrophobe, one hydrogen bond acceptor, and two ring aromatic features, demonstrated a high correlation between observed and predicted IC(50) values (r = 0.92). Validation of this pharmacophore was performed by predicting the IC(50) of a test set of commercially available (n = 19) and CP-320626-related (n = 48) CYP51 inhibitors. Using predictions below 10 microM as a cutoff indicative of active inhibitors, 16 of 19 commercially available inhibitors (84%) and 38 of 48 CP-320626-related inhibitors (79.2%) were predicted correctly. To better understand how inhibitors fit into the enzyme, potent CYP51 inhibitors were used to build a Cerius(2) receptor surface model representing the volume of the active site. This study has demonstrated the potential for ligand-based computational pharmacophore modeling of human CYP51 and enables a high-throughput screening system for drug discovery and data base mining.
    Drug Metabolism and Disposition 04/2007; 35(3):493-500. DOI:10.1124/dmd.106.013888 · 3.25 Impact Factor
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    • "The inhibition of CYP51 by conazoles would be expected to decrease serum cholesterol levels as reported for another CYP51 inhibitor (Harwood et al., 2005). We also observed, in a parallel study in mice, that all 3 conazoles decreased serum cholesterol levels (Allen et al., 2006). "
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    Toxicologic Pathology 02/2006; 34(7):879-94. DOI:10.1080/01926230601047824 · 2.14 Impact Factor
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    ABSTRACT: Type 2 diabetes (T2D) affects an increasing proportion of populations of both the developed and developing parts of the world. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 17 million Americans - 6.2% of the U.S. population - have diabetes, and more than one third of these are undiagnosed. Another 16 million have insulin resistance or pre-diabetes. Worldwide figures are even more staggering: in 2000 the World Health Organization (WHO) reported a worldwide incidence of 154.4 million diabetes patients. Hence, intense efforts towards the discovery and development of more efficacious and safer diabetes therapies are underway in academic and industrial research organizations. Since the appearance of the last review of diabetes in Annual Reports in Medicinal Chemistry in 2000, sales of troglitazone, the first peroxisome proliferator of activated receptor gamma (PPAR-γ) agonist on the market, were halted due to hepatotoxicity in a small number of patients. Two more potent new PPAR-γ agonists, rosiglitazone and pioglitazone were introduced and appear to be free of the hepatic liability associated with troglitazone. One other new molecular entity (NME) is Starlix, an ATP-sensitive pancreatic potassium channel inhibitor. However, there have been many significant developments in the discovery and development of novel molecular entities that are in various phases of clinical and preclinical development. These recent developments (post 2000) discussed in this chapter, can be broadly classified into 1) enhancers of insulin release, 2) enhancers of insulin action, 3) inhibitors of hepatic glucose production, 4) inhibitors of glucose absorption from the gut.
    Annual reports in medicinal chemistry 01/2005; 40:167-181. DOI:10.1016/S0065-7743(05)40011-1 · 1.36 Impact Factor
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