Epix Pharmaceuticals

Cambridge, MA, United States

Epix Pharmaceuticals

Cambridge, MA, United States
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Lobbes M.B.I.,Maastricht University | Heeneman S.,Maastricht University | Passos V.L.,Maastricht University | Welten R.,Atrium Medical | And 9 more authors.
Investigative Radiology | Year: 2010

Objective: To investigate the potential of gadofosveset-enhanced MR imaging for the characterization of human carotid atherosclerotic plaques. Materials and methods: Sixteen (9 symptomatic, 7 asymptomatic) patients with 70% to 99% carotid stenosis (according to NASCET criteria) were included (13 men, 3 women, mean age 67.6 years). All patients underwent baseline precontrast MR imaging of the carotid plaque. Immediately after completion of the baseline examination, 0.03 mmol/kg gadofosveset was administered. At 24 hours postinjection, the acquisition was repeated. Twelve patients were scheduled for carotid endarterectomy. Carotid endarterectomy specimens were HE-, CD31-, CD68-, and albumin-stained to correlate signal enhancement with plaque composition, intraplaque microvessel density, and macrophage and albumin content. A random intercept model was used to compare signal enhancement between symptomatic and asymptomatic patients, adjusting for size of various plaque components. This study was approved by the institutional medical ethics committee. All participants gave written informed consent. Results: Signal enhancement (SE) of the plaque was significantly higher in symptomatic patients compared with asymptomatic patients (median log SE 0.182 vs.-0.109, respectively, P < 0.001). A positive association (as expressed by a regression coefficient β = 0.0035) was found between signal enhancement on the log scale and intraplaque albumin content (P = 0.038). There was no association between signal enhancement and various other plaque components. Conclusion: In this study, the potential of gadofosveset-enhanced human carotid plaque MR imaging for identification of high-risk plaques was demonstrated. Signal enhancement of the plaque after administration of gadofosveset was associated with differences in intraplaque albumin content. Although promising, we emphasize that these results are based on a small patient population. Larger prospective studies are warranted. Copyright © 2010 by Lippincott Williams & Wilkins.

Hudson R.P.,University of Toronto | Chong P.A.,University of Toronto | Protasevich I.I.,University of Alabama at Birmingham | Vernon R.,University of Toronto | And 10 more authors.
Journal of Biological Chemistry | Year: 2012

Deletion of Phe-508 (F508del) in the first nucleotide binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to defects in folding and channel gating. NMR data on human F508del NBD1 indicate that an H620Q mutant, shown to increase channel open probability, and the dual corrector/potentiator CFFT-001 similarly disrupt interactions between β-strands S3, S9, and S10 and the C-terminal helices H8 and H9, shifting a preexisting conformational equilibrium from helix to coil. CFFT-001 appears to interact with β-strands S3/S9/S10, consistent with docking simulations. Decreases in Tm from differential scanning calorimetry with H620Q or CFFT-001 suggest direct compound binding to a less thermostable state of NBD1. We hypothesize that, in full-length CFTR, shifting the conformational equilibrium to reduce H8/H9 interactions with the uniquely conserved strands S9/S10 facilitates release of the regulatory region from the NBD dimerization interface to promote dimerization and thereby increase channel open probability. These studies enabled by our NMR assignments for F508del NBD1 provide a window into the conformational fluctuations within CFTR that may regulate function and contribute to folding energetics. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

Thibodeau P.H.,University of Texas Southwestern Medical Center | Thibodeau P.H.,University of Pittsburgh | Richardson III J.M.,University of Texas Southwestern Medical Center | Wang W.,University of Alabama at Birmingham | And 10 more authors.
Journal of Biological Chemistry | Year: 2010

The deletion of phenylalanine 508 in the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator is directly associated with >90% of cystic fibrosis cases. This mutant protein fails to traffic out of the endoplasmic reticulum and is subsequently degraded by the proteasome. The effects of this mutation may be partially reversed by the application of exogenous osmolytes, expression at low temperature, and the introduction of second site suppressor mutations. However, the specific steps of folding and assembly of full-length cystic fibrosis transmembrane conductance regulator (CFTR) directly altered by the disease-causing mutation are unclear. To elucidate the effects of the ΔF508 mutation, on various steps in CFTR folding, a series of misfolding and suppressor mutations in the nucleotide binding and transmembrane domains were evaluated for effects on the folding and maturation of the protein. The results indicate that the isolated NBD1 responds to both the ΔF508 mutation and intradomain suppressors of this mutation. In addition, identification of a novel second site suppressor of the defect within the second transmembrane domain suggests that ΔF508 also effects interdomain interactions critical for later steps in the biosynthesis of CFTR. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Porvasnik S.L.,University of Florida | Germain S.,University of Florida | Embury J.,University of Florida | Gannon K.S.,Eolas Biosciences United States | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Pulmonary arterial hypertension (PAH) is a life-threatening disease that results in right ventricular failure. 5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4- ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile monofumarate (PRX-08066) is a selective 5-hydroxytryptamine receptor 2B (5-HT2BR) antagonist that causes selective vasodilation of pulmonary arteries. In the current study, the effects of PRX-08066 were assessed by using the monocrotaline (MCT)-induced PAH rat model. Male rats received 40 mg/kg MCT or phosphate-buffered saline and were treated orally twice a day with vehicle or 50 or 100 mg/kg PRX-08066 for 5 weeks. Pulmonary and cardiac functions were evaluated by hemodynamics, heart weight, magnetic resonance imaging (MRI), pulmonary artery (PA) morphology, and histology. Cardiac MRI demonstrated that PRX-08066 (100 mg/kg) significantly (P < 0.05) improved right ventricular ejection fraction. PRX-08066 significantly reduced peak PA pressure at 50 and 100 mg/kg (P < 0.05 and < 0.01, respectively) compared with MCT control animals. PRX-08066 therapy also significantly reduced right ventricle (RV)/body weight and RV/left ventricle + septum (P < 0.01 and < 0.001, respectively) compared with MCT-treated animals. Morphometric assessment of pulmonary arterioles revealed a significant reduction in medial wall thickening and lumen occlusion associated with both doses of PRX-08066 (P < 0.01). The 5-HT2BR antagonist PRX-08066 significantly attenuated the elevation in PA pressure and RV hypertrophy and maintained cardiac function. Pulmonary vascular remodeling was also diminished compared with MCT control rats. PRX-08066 prevents the severity of PAH in the MCT rat model. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

Zhang Z.,Harvard University | Kolodziej A.F.,Epix Pharmaceuticals | Greenfield M.T.,Epix Pharmaceuticals | Caravan P.,Harvard University
Angewandte Chemie - International Edition | Year: 2011

Kept within bounds: For peptide-targeted contrast agents, internal motion limits the relaxivity gain. A focused library approach identified an N-terminal thymine peptide nucleic acid (PNA) that reaches an additional binding pocket on the protein fibrin. The heteroditopic binding rigidifies the molecule upon binding, resulting in increased protein-bound relaxivity (see picture). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dumas S.,Epix Pharmaceuticals | Jacques V.,Epix Pharmaceuticals | Sun W.-C.,Epix Pharmaceuticals | Troughton J.S.,Epix Pharmaceuticals | And 5 more authors.
Investigative Radiology | Year: 2010

Rationale and Objectives: The donor atoms that bind to gadolinium in contrast agents influence inner-sphere water exchange and electronic relaxation, both of which determine observed relaxivity. The effect of these molecular parameters on relaxivity is greatest when the contrast agent is protein bound. We sought to determine an optimal donor atom set to yield high relaxivity compounds. Methods: A total of 38 gadolinium-1,4,7,10-tetraazacyclo-dodecane-N, N′,N′′,N′′′-tetraacetato derivatives were prepared and relaxivity was determined in the presence and absence of human serum albumin as a function of temperature and magnetic field. Each compound had a common albumin-binding group and differed only by substitution of different donor groups at one of the macrocycle nitrogens. Oxygen-17 isotope relaxometry at 7.05 T was performed to estimate water exchange rates. Results: Changing a single donor atom resulted in changes in water exchange rates ranging across 3 orders of magnitude. Donor groups increased water exchange rate in the order: phosphonate ∼ phenolate > α-substituted acetate > acetate > hydroxamate ∼ sulfonamide > amide ∼ pyridyl ∼ imidazole. Relaxivites at 0.47 and 1.4 T, 37°C, ranged from 12.3 to 55.6 mMs and from 8.3 to 32.6 mMs respectively. Optimal relaxivities were observed when the donor group was an α-substituted acetate. Electronic relaxation was slowest for the acetate derivatives as well. Conclusions: Water exchange dynamics and relaxivity can be predictably tuned by choice of donor atoms. © 2010 by Lippincott Williams & Wilkins.

Jacques V.,Epix Pharmaceuticals | Dumas S.,Epix Pharmaceuticals | Sun W.-C.,Epix Pharmaceuticals | Troughton J.S.,Epix Pharmaceuticals | And 3 more authors.
Investigative Radiology | Year: 2010

Rationale and Objectives: The observed relaxivity of gadolinium-based contrast agents has contributions from the water molecule(s) that bind directly to the gadolinium ion (inner-sphere water), long-lived water molecules and exchangeable protons that make up the second-sphere of coordination, and water molecules that diffuse near the contrast agent (outer-sphere). Inner-and second-sphere relaxivity can both be increased by optimization of the lifetimes of the water molecules and protons in these coordination spheres, the rotational motion of the complex, and the electronic relaxation of the gadolinium ion. We sought to identify new high-relaxivity contrast agents by systematically varying the donor atoms that bind directly to gadolinium to increase inner-sphere relaxivity and concurrently including substituents that influence the second-sphere relaxivity. Methods: Twenty gadolinium-1,4,7,10-tetraazacyclo- dodecane-N,N′,N″,N′″-tetraacetato derivatives were prepared and their relaxivity determined in presence and absence of human serum albumin as a function of temperature and magnetic field. Data was analyzed to extract the underlying molecular parameters influencing relaxivity. Each compound had a common albumin-binding group and an inner-sphere donor set comprising the 4 tertiary amine N atoms from cyclen, an α-substituted acetate oxygen atom, 2 amide oxygen atoms, an inner-sphere water oxygen atom, and a variable donor group. Each amide nitrogen was substituted with different groups to promote hydrogen bonding with second-sphere water molecules. Results: Relativities at 0.47 and 1.4 T, 37°C, in serum albumin ranged from 16.0 to 58.1 mM-1s-1 and from 12.3 to 34.8 mM-1s -1, respectively. The reduction of inner-sphere water exchange typical of amide donor groups could be offset by incorporating a phosphonate or phenolate oxygen atom donor in the first coordination sphere, resulting in higher relaxivity. Amide nitrogen substitution with pendant phosphonate or carboxylate groups increased relaxivity by as much as 88% compared with the N-methyl amide analog. Second-sphere relaxivity contributed as much as 24 and 14 mM-1s-1 at 0.47 and 1.4 T, respectively. Conclusions: Water/proton exchange dynamics in the inner-and second-coordination sphere can be predictably tuned by choice of donor atoms and second-sphere substituents, resulting in high-relaxivity agents. © 2010 by Lippincott Williams & Wilkins.

Zhang Z.,Harvard University | Kolodziej A.F.,Epix Pharmaceuticals | Qi J.,Epix Pharmaceuticals | Nair S.A.,Epix Pharmaceuticals | And 6 more authors.
New Journal of Chemistry | Year: 2010

A strategy for preparing high relaxivity, metabolically-stable, peptide-based MR contrast agents is described. © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Spuentrup E.,University of Cologne | Spuentrup E.,RWTH Aachen | Wiethoff A.J.,EPIX Pharmaceuticals | Parsons E.C.,EPIX Pharmaceuticals | And 2 more authors.
European Journal of Radiology | Year: 2010

Purpose: The purpose of this study was to investigate the feasibility of clot visualization in small sinus and cortical veins with contrast enhanced MRA in a cerebral venous thrombosis animal model using a blood pool contrast agent, Gadofosveset, and high spatial resolution imaging. Material and methods: For induction of cerebral venous thrombosis a recently developed combined interventional and microsurgical model was used. Cerebral sinus and cortical vein thrombosis was induced in six pigs. Two further pigs died during the procedure. Standard structural, time-of-flight- and phase contrast-angiograms were followed by fast time resolved high resolution 3D MRA (4D MRA) and subsequent high spatial resolution 3D MRA in the equilibrium phase with and without addition of parallel imaging. Visualization of the clots using the different sequences was subjectively compared and contrast-to-noise ratio (CNR) was assessed. Results: In the remaining six animals the procedure and MR-imaging protocol including administration of Gadofosveset was successfully completed. The 3D high resolution MRA in the equilibrium phase without the addition of parallel imaging was superior to all the other applied MR measurement techniques in terms of visualization of the clots. Only applying this sequence bridging vein thromboses were also seen as a small filling defect with a high CNR of >18. Conclusion: Only the non-accelerated high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset allows for high-contrast visualization of very small clots in the cerebral sinus and cortical veins. Statement clinical impact: Detection of cortical vein thrombosis is of high clinical impact. Conventional MRI sequences often fail to visualize the clot. We could demonstrate that, in contrast to conventional sequences, with high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset very small clots in the cerebral sinus and cortical veins could be successfully visualized. We think that with the presented approach cortical vein thrombosis might also be sufficiently visualized in patients. © 2009 Elsevier Ireland Ltd. All rights reserved.

Kolodziej A.F.,EPIX Pharmaceuticals | Zhang Z.,EPIX Pharmaceuticals | Overoye-Chan K.,Massachusetts General Hospital | Jacques V.,EPIX Pharmaceuticals | Caravan P.,EPIX Pharmaceuticals
Methods in Molecular Biology | Year: 2014

Peptides are highly selective, high-affinity ligands for a diverse array of disease targets, but suitably derivatizing them for application as diagnostic or therapeutic agents often presents a significant challenge. Covalent modification with metal chelates frequently results in decreased binding affinity, so a variety of strategies must be explored to find suitable locations for modification and facile peptide conjugation chemistries that maintain or enhance binding affinity. In this chapter, we present a paradigm for systematically optimizing peptide binding and determining the favorable sites and methods for peptide conjugation. This strategy is illustrated by two case studies of peptide-based targeted gadolinium contrast agents: EP-2104R for diagnosis of thrombosis and EP-3533 for diagnosis of cardiac perfusion and fibrosis. Two different architectures for the peptide-metal complex conjugation were designed: EP-2104R contains a total of four gadolinium (Gd) chelates linked at the N-and C-termini, whereas EP-3533 is derivatized with three Gd chelates, two on the N-terminus and one on a lysine side chain. Detailed protocols are provided for two Gd chelate conjugation methods. © 2014 Springer Science+Business Media, LLC.

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