Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone.

Vatiquinone is a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich's ataxia. The objective of this analysis was to determine the effect of a cytochrome P450 isoform 3A4 (CYP3A4) inhibitor and inducer on vatiquinone pharmacokinetics (PKs). The coadministration of 400 mg of vatiquinone with 200 mg of itraconazole (a CYP3A4 inhibitor) resulted in increased maximum observed concentration (C) of vatiquinone and systemic exposure (AUC) by approximately 3.

Absorption, distribution, metabolism and excretion of C-vatiquinone in rats, dogs, and human subjects.

Vatiquinone is a potent inhibitor of 15-lipoxygenase and is in clinical development for the treatment of mitochondrial diseases and other disorders characterised by high levels of oxidative stress and dysregulation of energy metabolism.In rats, C-vatiquinone-derived radioactivity was quickly and widely distributed throughout the body and cleared from most tissues by 24 h post-dose following a single oral dose of C-vatiquinone.Following oral administration, 94% of dose was recovered within seven days in rats, approximately 61% of dose was recovered within seven days in dogs and approximately 93% of dose was recovered within nine days in human subjects (IND 119220).

Clinical Drug-Drug Interaction Between Vatiquinone, a 15-Lipoxygenase Inhibitor, and Rosuvastatin, a Breast Cancer Resistance Protein Substrate.

Vatiquinone is a small-molecule inhibitor of 15-lipoxygenase in phase 3 development for patients with mitochondrial disease and Friedreich ataxia. The objective of this analysis was to determine the effect of vatiquinone on the pharmacokinetic profile of rosuvastatin, a breast cancer resistance protein substrate. In vitro investigations demonstrated potential inhibition of BCRP by vatiquinone (half maximal inhibitory concentration, 3.

Evaluation of vatiquinone drug-drug interaction potential in vitro and in a phase 1 clinical study with tolbutamide, a CYP2C9 substrate, and omeprazole, a CYP2C19 substrate, in healthy subjects.

Purpose: In this study, the drug-drug interaction potential of vatiquinone with cytochrome P450 (CYP) substrates was investigated in both in vitro and clinical studies.

Methods: The inhibitory potential of vatiquinone on the activity of CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 was assessed in vitro. In an open-label, drug-drug interaction study in 18 healthy human subjects, a single oral dose of 500 mg tolbutamide and 40 mg omeprazole was administered on day 1, followed by a washout of 7 days.

Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity.

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.

Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease.

While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy.

EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome.

Background: Genetically defined Leigh syndrome is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. No treatment is available. EPI-743 is a novel small molecule developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases.

Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy.

Objective: To evaluate the safety and efficacy of a new therapeutic agent, EPI-743, in Leber hereditary optic neuropathy (LHON) using standard clinical, anatomic, and functional visual outcome measures.

Design: Open-label clinical trial.

Setting: University medical center.

Initial experience in the treatment of inherited mitochondrial disease with EPI-743.

Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study.

α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging.

We report that α-tocotrienol quinone (ATQ3) is a metabolite of α-tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging. ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling.

The effect of mechanical forces (vibration or external compression) on the dermal water content of the upper dermis and epidermis, assessed by high frequency ultrasound.

An ultrasound scanner, is used to detect changes in water content of the upper dermis. This has previously been found to vary with age and to show diurnal variation. Furthermore, oedema due to venous disease can be shown, using this technique, to respond to elevation.

Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2.

Role of LXRs in control of lipogenesis.

The discovery of oxysterols as the endogenous liver X receptor (LXR) ligands and subsequent gene targeting studies in mice provided strong evidence that LXR plays a central role in cholesterol metabolism. The identification here of a synthetic, nonsteroidal LXR-selective agonist series represented by T0314407 and T0901317 revealed a novel physiological role of LXR. Oral administration of T0901317 to mice and hamsters showed that LXR activated the coordinate expression of major fatty acid biosynthetic genes (lipogenesis) and increased plasma triglyceride and phospholipid levels in both species.

Ring constrained analogues of beta-alanine-containing GPIIb/IIIa receptor antagonists.

A series of ring constrained analogues of the GPIIb/IIIa receptor antagonist XR299 (1) was investigated as potential inhibitors of glycoprotein IIb/IIIa, a platelet receptor that plays a key role in platelet aggregation and platelet adhesion. Ring size was found to have a large effect on in vitro potency. Selected compounds showed good in vitro activity, a preference for binding to activated platelets, and modest duration of action when dosed i.

Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1.

Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation.

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action.

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets.

Prothrombin activation in rabbits.

The suitability of rabbit prothrombin activation fragment F 1.2 as a marker for the activation of the coagulation system was tested. Monoclonal antibodies to rabbit F 1.

Column switching in high-performance liquid chromatography with tandem mass spectrometric detection for high-throughput preclinical pharmacokinetic studies.

A high-throughput liquid chromatography-tandem mass spectrometry method is described for the determination of multiple compounds in dog and rat plasma. After acetonitrile precipitation of plasma proteins, the analytes are pre-concentrated and back-flushed on a reversed-phase column for separation using a switching valve. The analytes are ionized using TurboIon Spray in a positive mode, and detected by multiple reaction monitoring.

Antiplatelet efficacy of XV459, a novel nonpeptide platelet GPIIb/IIIa antagonist: comparative platelet binding profiles with c7E3.

Recent advances in the development of i.v. platelet glycoprotein alphaIIb/beta3 integrin (GPIIb/IIIa) antagonists led to the development of either a class of small-molecular-weight antagonists with a short to ultra-short duration of antiplatelet effects (Integrelin, Tirofiban, DMP728) or a very long-acting antagonist (ReoPro).

Oral antiplatelet efficacy and specificity of a novel nonpeptide platelet GPIIb/IIIa receptor antagonist, DMP 802.

This study was undertaken to define the platelet glycoprotein alphaIIb beta3 integrin (GPII/IIIa) affinity, specificity, and oral antiplatelet efficacy of DMP 802, a small-molecule nonpeptide antiplatelet agent. Platelet GPIIb/IIIa integrin binding affinity and specificity for DMP 802 were determined by using binding and adhesion assays with cells from various species, including human. DMP 802 demonstrated a potent antiplatelet efficacy [median inhibitory concentration (IC50), 0.

Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists.

Using isoxazoline XR299 (1a) as a starting point for the design of highly potent, long-duration GPIIb/IIIa antagonists, the effect of placing lipophilic substituents at positions alpha and beta to the carboxylate moiety was evaluated. Of the compounds studied, it was found that the n-butyl carbamate 24u exhibited superior potency and duration of ex vivo antiplatelet effects in dogs. Replacement of the benzamidin-4-yl moiety with alternative basic groups, elimination of the isoxazoline stereocenter, and reversal of the orientation of the isoxazoline ring resulted in lowered potency and/or duration of action.

Novel nonpeptide antiplatelet glycoprotein IIb/IIIa receptor antagonist, DMP754: receptor binding affinity and specificity.

Objective: To define the antiplatelet efficacy and specificity of the glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist prodrug DMP754 and its free acid form, XV459.

Methods And Materials: DMP754 has an IC50 > 1 mumol/l, and, upon its conversion with esterases to its free acid form, demonstrated high potency (IC50 20-45 nmol/l) in inhibiting human platelet aggregation induced by 10 mumol/l adenosine diphosphate, 20 micrograms/ml collagen, 1 mmol/l epinephrine, 10 mumol/l platelet activating factor or 0.5 IU/ml thrombin.

A monoclonal antibody that recognizes the GPIIb/IIIa antagonist DMP 728. Reversal of the effects of DMP 728 on platelet aggregation and bleeding time in the dog.

Since hemorrhagic events represent a major safety concern associated with the use of new antithrombotic therapies such as glycoprotein (GP) IIb/IIIa receptor blockade, we evaluated the ability of a monoclonal antibody recognizing DMP 728 (cyclic [D-2-aminobutyryl-N2-methyl-L-argininyl-glycyl-L-aspartyl-3- aminomethyl-benzoic acid] methanesulfonic acid salt), a potent GPIIb/IIIa receptor antagonist, to reverse the pharmacological actions of DMP 728 in the dog. DC11 was chosen for in vivo evaluation based on its ability to inhibit the binding of [3H]DMP 728 to activated platelets and to attenuate the inhibition of ADP-induced aggregation on platelet-rich plasma ex vivo by DMP 728. After anesthesia mongrel dogs were given DMP 728 (20 micrograms/kg body wt IV) infused into the femoral vein, bleeding times were determined using a Simplate device from incisions on the backside of the tongue, and platelet aggregation was determined ex vivo.

Preservation of regional and global left ventricular function by intracoronary infusion with oxygenated fluorocarbon emulsion Therox in dogs.

We tested the oxygen transport and delivery capacity of the novel perfluorocarbon emulsion, Therox (F44E, 1,2-bis-perfluorobutyl-ethylene) by comparing left ventricular regional and global function in dogs during perfusion of the left anterior descending coronary artery (LAD) with oxygenated Krebs buffer and oxygenated Therox emulsion (20% w/v) at 20 ml/min for two separate 3 min periods. During LAD perfusion with oxygenated Krebs buffer, complete loss of systolic wall thickening in the LAD perfusion area was observed, dP/dt was significantly reduced and left ventricular end-diastolic pressure (LVEDP) was increased. In contrast, LAD perfusion with oxygenated Therox maintained regional wall thickening at 60-70% of control and completely preserved global function as measured by dP/dt and LVEDP.