FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a long-acting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF-05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF-05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans.

In subjects with low HDL cholesterol levels, CETP inhibition with torcetrapib markedly increased HDL cholesterol levels and also decreased LDL cholesterol levels, both when administered as monotherapy and when administered in combination with a statin.

Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.

Objective-The ability of the potent cholesteryl ester transfer protein (CETP) inhibitor torcetrapib 414) to raise high-density lipoprotein cholesterol (HDL-C) levels in healthy young subjects was tested in this initial phase 1 multidose study. Methods and Results-Five groups of 8 subjects each were randomized to placebo (nϭ2) or torcetrapib (nϭ6) at 10, 30, 60, and 120 mg daily and 120 mg twice daily for 14 days. Torcetrapib was well tolerated, with all treated subjects completing the study. The correlation of plasma drug levels with inhibition (EC50ϭ43 nM) was as expected based on in vitro potency (IC50 Ϸ50 nM), and increases in CETP mass were consistent with the proposed mechanism of inhibition. CETP inhibition increased with escalating dose, leading to elevations of HDL-C of 16% to 91%. Total plasma cholesterol did not change significantly because of a reduction in nonHDL-C, including a 21% to 42% lowering of low-density lipoprotein cholesterol at the higher doses. Apolipoprotein A-I and E were elevated 27% and 66%, respectively, and apoB was reduced 26% with 120 mg twice daily. Cholesteryl ester content decreased and triglyceride increased in the nonHDL plasma fraction, with contrasting changes occurring in HDL. studies, the inverse correlation between high-density lipoprotein (HDL) levels and premature coronary heart disease (CHD) has been strengthened. A 1% decrease in HDL cholesterol (HDL-C) has been associated with a 1% to 2% increase in risk for CHD, 3 and lipid intervention trials have demonstrated that increases in HDL-C 4 and its main apoprotein, A-I, 5 contribute to reduced CHD, even in the absence of any change in low-density lipoprotein cholesterol (LDL-C). 6 However, current therapies for raising HDL are limited. The fibrates and statins produce only modest elevations in HDL, and the use of niacin, although somewhat more effective, has been hampered by side effects. 7 In a recent study, the combination of lovastatin and extended-release niacin (Advicor) was able to increase HDL levels by 20% to 32%, 8 but withdrawal rates for incidents of flushing and other adverse events were relatively high. Conclusions-TheseThe marked increase in HDL associated with human deficiency of cholesteryl ester transfer protein (CETP) 9 has See page 387 and cover suggested CETP inhibition as a means of elevating HDL. Expression of CETP in transgenic mice under different metabolic settings has produced mixed results regarding its atherogenicity, whereas inhibition of endogenous CETP in rabbits has more consistently been antiatherogenic. 10 With regard to human CETP mutations and the associated reduction in CETP levels, recent analysis of prospective data from the Honolulu Heart Study 10 is consistent with the results of a previous study of Japanese subjects 11 in concluding that CETP deficiency is protective when associated with HDL-C levels Ն60 mg/dL.The results for a phase 2 study testing the synthetic CETP inhibitor JTT-705 in subjects with mild hyperlipidemia have been reported. 12 At 900 mg daily, JTT-705 led to ...

We have identified a series of potent cholesteryl ester transfer protein (CETP) inhibitors, one member of which, torcetrapib, is undergoing phase 3 clinical trials. In this report, we demonstrate that these inhibitors bind specifically to CETP with 1:1 stoichiometry and block both neutral lipid and phospholipid (PL) transfer activities. CETP preincubated with inhibitor subsequently bound both cholesteryl ester and PL normally; however, binding of triglyceride (TG) appeared partially reduced. Inhibition by torcetrapib could be reversed by titration with both native and synthetic lipid substrates, especially TG-rich substrates, and occurred to an equal extent after long or short preincubations. The reversal of TG transfer inhibition using substrates containing TG as the only neutral lipid was noncompetitive, suggesting that the effect on TG binding was indirect. Analysis of the CETP distribution in plasma demonstrated increased binding to HDL in the presence of inhibitor. Furthermore, the degree to which plasma CETP shifted from a free to an HDL-bound state was tightly correlated to the percentage inhibition of CE transfer activity. The finding by surface plasmon resonance that torcetrapib increases the affinity of CETP for HDL by z5-fold likely represents a shift to a binding state that is nonpermissive for lipid transfer. In summary, these data are consistent with a mechanism whereby this series of inhibitors block all of the major lipid transfer functions of plasma CETP by inducing a nonproductive complex between the transfer protein and HDL. Despite the demonstration of the atheroprotective effects of HDL over the past several decades (1-4), no current therapy exists that is effective and well tolerated for increasing the levels of this lipoprotein (5). Although the use of extended-release niacin (Niaspan) at daily doses of 2 g or less has served to minimize the high incidence of vasodilatory effects, such as flushing and itching (6), toleration issues continue to limit compliance. Also, at 2 g/day, niacin increases high density lipoprotein cholesterol (HDL-C) by ,30% (7). The high levels of HDL associated with human cholesteryl ester transfer protein (CETP) deficiency (8) have suggested CETP inhibition as a means of increasing HDL. Although expression of human CETP in transgenic mice has produced mixed results regarding its atherogenicity, more consistent antiatherogenic effects have resulted from the inhibition of endogenous CETP in rabbits (8). In the wake of the beneficial effects observed through CETP inhibition in rabbits by induction of autoantibodies (9) and by administration of a synthetic inhibitor (10), these interventions have progressed to trials aimed at increasing HDL in humans. Although the use of the CETP vaccine has yet to demonstrate sufficient anti-CETP response to increase HDL (11), 900 mg/day of the inhibitor JTT-705 increased HDL-C by 34% and decreased low density lipoprotein cholesterol (LDL-C) by 7% (12).We have identified a new series of CETP inhibitors culminating in the dev...

The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp(3)-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.

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Background: Human cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high-density to low-density lipoprotein particles. Results: Crystallographic, mutagenesis, and biochemical studies illuminated inhibition mechanisms of CETP by torcetrapib and a structurally distinct compound, ((2R)-3-{[4-(4-chloro-3-ethylphenoxy)pyrimidin-2-yl][3-(1,1,2,2-tetrafluoroethoxy)benzyl]-amino}-1,1,1-trifluoropropan-2-ol. Conclusion: These small molecules inhibit CETP through blocking its lipid tunnel. Significance: Potential polar interactions at compound binding site may be utilized in design of inhibitors with improved physical properties.