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Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the U.S. Department of Energy (DOE) Office of Science (SC), the single largest supporter of basic research in the physical sciences in the United States. In support of SC programs, ESnet regularly updates and refreshes its understanding of the networking requirements needed by instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet to be a highly successful enabler of scientific discovery for over 25 years. In August 2013, ESnet and the DOE SC Offices of High Energy Physics (HEP) and Nuclear Physics (NP) organized a review to characterize the networking requirements of the programs funded by the HEP and NP program offices. Several key findings resulted from the review. Among them: 1. The Large Hadron Collider?s ATLAS (A Toroidal LHC Apparatus) and CMS (Compact Muon Solenoid) experiments are adopting remote input/output (I/O) as a core component of their data analysis infrastructure. This will significantly increase their demands on the network from both a reliability perspective and a performance perspective. 2. The Large Hadron Collider (LHC) experiments (particularly ATLAS and CMS) are working to integrate network awareness into the workflow systems that manage the large number of daily analysis jobs (1 million analysis jobs per day for ATLAS), which are an integral part of the experiments. Collaboration with networking organizations such as ESnet, and the consumption of performance data (e.g., from perfSONAR [PERformance Service Oriented Network monitoring Architecture]) are critical to the success of these efforts. 3. The international aspects of HEP and NP collaborations continue to expand. This includes the LHC experiments, the Relativistic Heavy Ion Collider (RHIC) experiments, the Belle II Collaboration, the Large Synoptic Survey Telescope (LSST), and others. The international nature of these collaborations makes them heavily reliant on transoceanic connectivity, which is subject to longer term service disruptions than terrestrial connectivity. The network engineering aspects of undersea connectivity will continue to be a significant part of the planning, deployment, and operation of the data analysis infrastructure for HEP and NP experiments for the foreseeable future. Given their critical dependency on networking services, the experiments have expressed the need for tight integration (both technically and operationally) of the domestic and the transoceanic parts of the network infrastructure that supports the experiments. 4. The datasets associated with simulations continue to increase in size, and the need to move these datasets between analysis centers is placing ever-increasing demands on networks and on data management systems at the supercomputing centers. In addition, there is a need to harmonize cybersecurity practice with the data transfer performance requirements of the science. This report expands on these points, and addresses others as well. The report contains a findings section in addition to the text of the case studies discussed during the review.

We evaluated the role of the melanocortin-4 receptor (MC-4R) in the control of metabolic rate and food intake in mice. Intraperitoneal administration of the non-selective MC-R agonist melanotan II (MT-II; a cyclic heptapeptide) increases metabolic rate in wildtype mice, while MC-4R knockout mice are insensitive to the effects of MT-II on metabolic rate. MC-4R knockout mice are also insensitive to the effects of MT-II on reducing food intake. We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited.

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.

In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation of the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action. In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation at the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action

The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan (3), which was derived from the screening lead N-ethyl-L-tryptophan benzyl ester, has been used as a starting point to identify high-affinity substance P receptor antagonists with improved in vivo activity. Altering the ester moiety to an amide or ether led to a substantial loss in binding affinity, but conversion to a ketone provided compounds with affinity comparable to the equivalent esters. A homochiral synthesis of the key intermediate amino ketone 15 was developed which allows its preparation on a large scale. From this intermediate a range of amine-containing acylamino derivatives were prepared with affinity optimized in the morpholinylbutyramide 161 which has an IC 50 of 0.17 nM at the human NK1 receptor. In addition to improving affinity, the amino group also provided aqueous solubility for a number of these derivatives. When tested in vivo the quinuclidine derivative L-737,488 (16i) was found to be an orally active (ID 50 = 1.8 mg/kg) inhibitor of substance P-induced dermal extravasation in the guinea pig.

HEP Science Network Requirements Office of High Energy Physics Network Requirements Workshop Conducted August 27 and 28, 2009 Final Report

perfSONAR is a web services-based infrastructure for collecting and publishing network performance monitoring. A primary goal of perfSONAR is making it easier to solve end-to-end performance problems on paths crossing several networks. It contains a set of services delivering performance measurements in a federated environment. These services act as an intermediate layer, between the performance measurement tools and the diagnostic or visualization applications. This layer is aimed at making and exchanging performance measurements across multiple networks and multiple user communities, using well-defined protocols. This paper summarizes the key perfSONAR components, and describes how they are deployed by the US-LHC community to monitor the networks distributing LHC data from CERN. All monitoring data described herein is publicly available, and we hope the availability of this data via a standard schema will inspire others to contribute to the effort by building network data analysis applications that use perfSONAR.

The Department of Energy's (DOE) Office of Science is the largest supporter of basic research in the physical sciences in the US. It directly supports the research of 15,000 PhDs, PostDocs and Graduate Students, and operates major scientific facilities at DOE laboratories that serve the entire US research community: other Federal agencies, universities, and industry, as well as the international research and education (R and E) community. ESnet's mission is to provide the network infrastructure that supports the mission of the Office of Science (SC). ESnet must evolve substantially in order to continue meeting the Office of Science mission needs and this paper discusses the development of ESnet's strategy to meet these requirements through a new network architecture and implementation approach.

The peptide leukotrienes LTC4, D4 and E4 collectively account for the biological activity known as slow-reacting substance of anaphylaxis (SRS-A). These metabolites of arachidonic acid are thought to play a role in lung pathophysiology. A role in asthma is postulated as a result of their potent bronchoconstrictor activity both in vitro (Dahlen et al. 1980; Drazen et al. 1980; Hanna et al. 1981; Piper et al. 1981; Jones et al. 1982; Peters et al. 1984) and in vivo (Manning et al. 1990; Holroyde et al. 1981; Griffin et al. 1983; Weiss et al. 1982; Barnes et al. 1984). Increased production of leukotrienes has been demonstrated following antigen challenge of the airways of allergic patients in vivo (Creticos et al. 1984; Ishihara et al. 1985; Isono et al. 1985) and in vitro (Dalhen et al. 1983).