Ellen A. Cannady

Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure

Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. These efforts, however, have been hampered by the fact that most CETP inhibitors either have low potency or have undesirable side effects. In this study, we describe a novel benzazepine compound evacetrapib (LY2484595), which is a potent and selective inhibitor of CETP both in vitro and in vivo. Evacetrapib inhibited human recombinant CETP protein (5.5 nM IC50) and CETP activity in human plasma (36 nM IC50) in vitro. In double transgenic mice expressing human CETP and apoAI, evacetrapib exhibited an ex vivo CETP inhibition ED50 of less than 5 mg/kg at 8 h post oral dose and significantly elevated HDL cholesterol. Importantly, no blood pressure elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data indicate that evacetrapib is a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II clinical development.

The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470)

The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.

Effects of the cholesteryl ester transfer protein inhibitor evacetrapib on lipoproteins, apolipoproteins and 24-h ambulatory blood pressure in healthy adults.

We investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of evacetrapib.

Design, synthesis and structure-activity-relationship of 1,5-tetrahydronaphthyridines as CETP inhibitors.

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.

A Multidose Study to Examine the Effect of Food on Evacetrapib Exposure at Steady State

Purpose: To determine the effect of a high-fat meal on evacetrapib exposure at steady state in healthy participants. Methods: This was a randomized, 2-period, 2-sequence, open-label, crossover study. Patients were randomly assigned to 1 of the 2 treatment sequences in which they received evacetrapib 130 mg/d for 10 days following a 10-hour fast each day or following a high-fat breakfast each day. Plasma samples collected through 24 hours were analyzed for evacetrapib concentrations and pharmacokinetic parameter estimates including area under the concentration–time curve during a dosing interval (AUCτ), maximum observed concentration (Cmax), and time of Cmax (tmax) were calculated. Pharmacodynamic parameters, including cholesteryl ester transfer protein (CETP) activity, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides, were also assessed. Results: A total of 34 males and 6 females, mean age 41.5 years and mean body mass index 26.6 kg/m2, were enrolled. Statistical analysis showed AUCτ was 44% higher (90% confidence interval [CI]: 29%-62%) and Cmax was 51% higher (90% CI: 28%-79%) in the fed state than in the fasted state, indicating an effect of food. Consistent with higher evacetrapib exposure, changes in HDL-C, LDL-C, and CETP activity appeared to be greater in the fed state than in the fasted state. There were no notable changes in total cholesterol or triglycerides following administration in the fed and fasted states. The 130-mg doses of evacetrapib were well tolerated with and without food. Conclusion: A high-fat meal increased evacetrapib mean exposure at steady state by 44% in healthy participants.

Mechanisms of ovotoxicity induced by environmental chemicals: 4-vinylcyclohexene diepoxide as a model chemical.

Females are born with a finite number of undeveloped, primordial follicles. Environmental chemicals that destroy oocytes contained in these follicles can produce premature ovarian failure (early menopause in women) because once destroyed, they cannot be replaced. Menopause is known to be associated with an increased incidence of a variety of health problems such as osteoporosis, cardiovascular disease, and ovarian cancer. Exposure of women to chemicals that are ovotoxic in laboratory animals (chemotherapeutic agents, contaminants of cigarette smoke) is known to be associated with early menopause. Therefore, an overall understanding of mechanisms involved in chemical-induced ovotoxicity is of general health-related concern (Hoyer and Sipes, 1996).

Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [13C8]-evacetrapib as a tracer

This open‐label, single‐period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130‐mg evacetrapib oral dose and 4‐h intravenous (IV) infusion of 175 µg [13C8]‐evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [13C8]‐evacetrapib using high‐performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration‐time curve (AUC) from zero to infinity (AUC[0‐∞]) and to the last measureable concentration (AUC[0‐tlast]), were calculated. Bioavailability was calculated as the ratio of least‐squares geometric mean of dose‐normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2–47.6%) for AUC(0‐∞) and 44.3% (90% CI: 41.8–46.9%) for AUC(0‐tlast). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a 13C‐labeled IV microdose tracer at about 1/1000th the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.

Evacetrapib: in vitro and clinical disposition, metabolism, excretion, and assessment of drug interaction potential with strong CYP3A and CYP2C8 inhibitors.

Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high‐risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug–drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100‐mg oral dose of 14C‐evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapibs CYP‐associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and 2.30% of the dose was excreted in feces and urine, respectively. In clinical DDI studies, the ratios of geometric least squares means for evacetrapib with/without the CYP3A inhibitor ketoconazole were 2.37 for area under the curve (AUC)(0–∞) and 1.94 for Cmax. There was no significant difference in evacetrapib AUC(0–τ) or Cmax with/without the CYP2C8 inhibitor gemfibrozil, with ratios of 0.996 and 1.02, respectively. Although in vitro results indicated that both CYP3A and CYP2C8 metabolized evacetrapib, clinical studies confirmed that evacetrapib is primarily metabolized by CYP3A. However, given the modest increase in evacetrapib exposure and robust clinical safety profile to date, there is a low likelihood of clinically relevant DDI with concomitant use of strong CYP3A or CYP2C8 inhibitors.

CYP‐mediated drug–drug interactions with evacetrapib, an investigational CETP inhibitor: in vitro prediction and clinical outcome

Aims Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as ‘add‐on’ therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug–drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated. Methods The DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic. Results In vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (K i) ranging from 0.57 µm (CYP2C9) to 7.6 µm (CYP2C19). Evacetrapib was a time‐dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co‐administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady‐state, with no differences in reported hepatic or muscular adverse events. Conclusions Taken together, the extent of CYP‐mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.

Design and synthesis of new tetrahydroquinolines derivatives as CETP inhibitors

This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.