Patent Highlights February–March 2017
2017; Future Science Ltd; Volume: 6; Issue: 4 Linguagem: Inglês
10.4155/ppa-2017-0016
ISSN2046-8962
Autores Tópico(s)Heme Oxygenase-1 and Carbon Monoxide
ResumoPharmaceutical Patent AnalystVol. 6, No. 4 Patent HighlightsFree AccessPatent highlights February–March 2017Hermann AM MuckeHermann AM MuckeE-mail Address: h.mucke@hmpharmacon.comH.M. Pharma Consultancy, 1160 Wien, AustriaPublished Online:11 Jul 2017https://doi.org/10.4155/ppa-2017-0016AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit A snapshot of noteworthy recent developments in the patent literature of relevance to pharmaceutical and medical research and development.First draft submitted: 18 April 2017; Accepted for publication: 20 April 2017; Published online: 11 July 2017WO/2017/017414New therapeutic compound and use in therapyInventor: Patient, LeeAssignee: Proximagen Ltd., Cambridgeshire, UKMeSH keywords: amine oxidase (copper-containing) • autoimmune diseases • cardiovascular diseases • cell adhesion molecules • diabetes mellitusThe inventors present {4-[3-(dimethylamino)propoxy]phenyl}methyl (4S)-4-(propan-2-yl)-3H,4H,5H,6H,7H-imidazo[4,5-c]pyridine-5-carboxylate, a novel inhibitor of semicarbazide-sensitive amine oxidase (SSAO), a copper-containing enzyme that is also known as vascular adhesion protein-1 (VAP-1) that oxidatively deaminates primary amines. SSAO/VAP-1 is expressed in vascular and nonvascular smooth muscle tissue, endothelium and adipose tissue, but is also found in plasma [1]. Reactive products of SSAO enzymatic action (aldehydes, hydrogen peroxides and ammonia) are thought to contribute to the progression of cardiovascular diseases [2], diabetic complications [3] and Alzheimer's disease [4]. SSAO inhibition would also reduce the adhesive capacity of immune cells and correspondingly their activation and final extravasation, giving inhibitors potential in inflammatory and autoimmune conditions [5]. The novel compound was tested in several well established murine models: collagen-induced arthritis, dextran sulfate-induced colitis, experimental allergic encephalomyelitis as a surrogate for multiple sclerosis, carbon tetrachloride-induced liver fibrosis, laser burn-induced choroidal neovascularization, and finally in a genetic model of Duchenne's muscular dystrophy. All models produced results that are attractive, or at least promising. Nothing is reported concerning selectivity with respect to monoamine oxidases, a factor that could be quite important for clinical development – which no SSAO inhibitor has reached yet.Published: 2 February 2017WO/2017/021319Broad-spectrum reactivators of OPNA-inhibition of human cholinesterasesInventors: Baati R, Brown RCD, Dias J, Nachon F, De Sousa JApplicants: Centre National de la Recherche Scientifique, Paris, France; Université de Strasbourg, Strasbourg, FranceMeSH keywords: cholinesterase reactivators • nerve agents • organophosphatesOrganophosphorus nerve agents act by phosphorylating the catalytic serine residue in the active center of cholinesterase enzymes, overloading cholinergic synapses with acetylcholine and chronically overstimulating muscarinic and nicotinic receptors. Although the public usually associates this class with chemical warfare agents (tabun, sarin, soman, VX), agricultural pesticides (paraoxon, parathion, tetraethyl pyrophosphate, and dozens of others) claim a far larger human toll, especially when used by insufficiently trained and incompletely protected workforce with spotty monitoring: an estimated 3 million acute intoxications occur per year, 200,000 of them fatal because the body cannot replace the nonfunctional cholinesterases quickly enough, even if the agent is completely removed. While antimuscarinics and anticonvulsants constitute the classical first aid measure, the only way to address the root problem is to remove phosphorylation, which can be accomplished by pyridinium oximes or aldoximes. Efforts to broaden the efficacy spectrum of such cholinesterase reactivators have been going on for a long time [6–8]. Recently, the inventors synthesized bifunctional reactivators where a tetrahydroacridine-type moiety is tethered to an oxime via a flexible linker (see Kliachyna et al. [9] and WO/2015/075082); the purpose of this tacrine-type element is to act as a peripheral site ligand that increases the affinity of the reactivator for the enzyme. With the present invention they have improved on these constructs by replacing the tacrine moiety with aminoquinoline – a slightly simpler structure which is not known to bind to the peripheral ligand site of cholinesterases. The compounds – for example, (Z)-3-hydroxy-6-(3-(pyridin-4-ylamino)propyl)picolinaldehyde oxime – outperformed most reactivators for VX- and tabun-inhibited human acetylcholinesterases. In addition they (reversibly) inhibit those native enzymes at micro- to nanomolar concentrations, making them potential candidates to treat Alzheimer's disease.Published: 9 February 2017WO/2017/023684Covalent irreversible inhibitors of Usp7 as anti-cancer agentsInventors: Weinstock J, Wu J, Kizhakkethil-George SK, Wang F, Kodrasov MP, Agarwal SApplicant: Progenra, Inc., Malvern, PA, USAMeSH keywords: DNA-binding proteins • neoplasms • ubiquitin-specific proteasesUsp7 deubiquitinates and stabilizes tumor suppressors (including p53), DNA repair proteins, cytokines, viral proteins and epigenetic modulators [10]. Many of these substrates as well as Usp7 are highly expressed in a variety of cancers and their downregulation inhibits tumor growth. Usp7 inhibitor treatment results in downregulation of Usp7 substrates including a DNA methyltransferase (Dnmt1), a ubiquitin-like protein containing PHD and RING finger domains (Uhrf1) and the Foxp3 transcription factor, leading to inactivation and or downregulation of regulatory T cells, and activation of effector T cells. Few small molecules with low-micromolar inhibitory activity have been reported, including HBX 41,108 (Hybrigenics Pharma, Paris, France) [11], P22077 [12], and a series of thiazoles [13]. The inventors present nitrothiophene-2-carboxamides which build on the thiophenes disclosed by the applicant in WO/2010/114881. They form a covalent adduct with wild-type Usp7 (but not with the C223A mutant enzyme, indicating that this active site cysteine is necessary for the adduct formation), resulting in profound inhibition of activity in cultured cells even 72 h after a 2-h exposure to 5-[(3,5-dichloropyridin-4-yl)sulfanyl]-N-[3-(methylsulfonyl)phenyl]-4-nitrothiophene-2-carboxamide at 10 μM. In Jurkat cells after 24 h treatment, these inhibitors decreased Dnmt1, Uhrf1 and Hdm2 in a dose-dependent manner. For the inventors' most recent work on Usp7 see Wang et al. [14].Published: 9 February 2017WO/2017/025298Cross-linked star-shaped self-assembled polypeptides and its use as carriers in biomedical applicationsInventors: Vincent Docón MJ, Duro Castaño A, Nebot Carda VJApplicant: Centro de Investigación Príncipe Felipe, Valencia, SpainMeSH keywords: nanoconjugates • polymersImproved understanding of cellular internalization mechanisms has led to polymeric nanocarriers with specific shapes that can serve as optimized drug vehicles. 'Star' polymers, which consist of various linear chains linked to a central core, can be augmented with multifunctional moieties that act as cross-linkers [15]. Besides allowing the rheological and thermoplastic properties to be engineered, this enables reversible self-assembly in solution. The resulting micellar structures can encapsulate and deliver hydrophobic drugs for passive tumor targeting [16]; and if their connecting elements contain enzymatically or reductively degradable spacers they can be made biodegradable [17]. The present invention relates to 3-arm star-shaped polypeptide derivatives consisting of a 1,3,5-benzenetricarboxamide core as the initiator for the ring opening polymerization of N-carboxyanhydride monomers and three arms with a polypeptide backbone (mostly polyglutamate). Their self-assembly yields structures with a gyration radius in the range of 70–160 nm. Post-polymerization modifications of the polypeptide residues with cross-linking groups stabilizes these nanostructures, which can be further functionalized using click chemistry. Small angle nuclear scattering confirmed that these nanostructures resemble hard spheres with branches pointing outside. Fluorescent (e.g., Oregon Green cadaverine) or radioactive (111In) labels can be easily introduced, creating the additional option of acting as imaging tracers. The lysosomal protease cathepsin B degrades the polypeptide arms regardless of their complex architecture, in vitro and (as live-cell confocal microscopy with cathepsin inhibitors show) also after cellular uptake, which is more efficient with the linear equivalents. For the peer review companion papers see Duro Castaño et al. [18,19].Published: 16 February 2017WO/2017/025889Polymeric nanoparticles with DEC-205 ligand and co-encapsulating an antigen subject to an autoimmune responseInventors: Benson MJ, Darvari R, Edmonds JN, Look MW-H, Pak RHApplicant: Pfizer, Inc., NY, USAMeSH keywords: DEC-205 receptors • dendritic cells • nanocapsules • polymers • recombinant proteinsThe single greatest drawback with recombinant protein therapy is the inherent immunogenicity of these biotechnology drugs. This is most pronounced with hemophilia A, where 25–30% of patients develop neutralizing antibodies to the factor VIII replacement products which they constantly need [20,21]. This invention attempts to solve the problem by providing a polymeric nanoparticle (most preferably, 60–300 nm in diameter) that co-encapsulates the therapeutic protein with a glucocorticoid receptor agonist (most preferably, betamethasone-17-valerate or betamethasone-17,21-dipropionate). A subpopulation of the polymer chains making up the shell is functionalized with a reactive group in order to covalently attach a targeting ligand for DEC-205 (preferably, a monoclonal antibody fragment) to the exterior of the particles. DEC-205 is a C-type multilectin surface protein expressed primarily by interdigitating dendritic cells in T-cell areas of lymphoid tissues, bone marrow-derived dendritic cells, Langerhans cells, and at low levels on macrophages and T cells. Together with DEC-205 targeting, the glucocorticoid receptor agonist ensures that a tolerogenic response to the antigen, rather than an immunogenic response, is induced [22]. In vitro data are presented for constructs loaded with B-domain deleted factor VIII (1.5% w/w) and betamethasone dipropionate (9.4% w/w); in vivo data are for particles containing myelin oligodendrocyte glycoprotein and betamethasone dipropionate, which attenuated myelin oligodendrocyte glycoprotein-specific antibodies in mice challenged with Complete Freud's Adjuvant. Earlier work from a different group had used rapamycin as the tolerogenic immunomodulator, without DEC-205 targeting [23].Published: 16 February 2017WO/2017/031116Small molecule inhibitors of Ku70/80 and uses thereofInventors: Weterings E, Mahadevan D, Vagner JApplicant: The Arizona Board of Regents on behalf of the University of Arizona, Tucson, AZ, USAMeSH keywords: DNA end-joining repair • DNA-binding proteins • Ku autoantigenThe Ku70 and Ku80 proteins are the DNA-binding components of the DNA-dependent protein kinase (DNA-PK), a crucial element in the Non-Homologous End-Joining (NHEJ) pathway which is predominant in the repair of DNA double strand breaks (DSBs) in human cells [24,25]. The NHEJ pathway is frequently upregulated in several solid tumors as a compensatory mechanism for a separate DSB repair defect or for innate genomic instability, making this pathway a powerful target for synthetic lethality approaches that re-sensitize tumors to chemo- or radiation therapy. The inventors have discovered a novel prospective ligand binding pocket in the Ku70/80 crystal structure [26,27]. Computational screening of small molecule libraries identified nine compounds with a predicted fit to the prospective pocket. These compounds were subsequently tested at 100 μM in an electrophoretic mobility shift assay with a radioactively labeled artificial DNA substrate and purified Ku70/80 protein, followed by nondenaturing gel electrophoresis. Two compounds (ZINC 09009828 and Vitas-M STL127705) were found capable of disrupting the binding of Ku to DNA as well as the activation of DNA-PKs, thereby effectively blocking the first two critical steps of the NHEJ process. Most importantly, they synergistically sensitized human SF-767 glioblastoma cells to radiation treatment at sub-cytotoxic concentrations, indicating a clear potential to diminish DSB repair. The Vitas-M compound was well tolerated by nude mice when given as a 5 mg/kg i.p. bolus, and had a plasma half-life of approximately 1.5 h. Several of its structural analogs were also investigated; JV761 had an IC50 of 12 μM for Ku-dependent activation of DNA-PK, and sensitized SF-767 cells to radiation at much lower concentrations than the parent compound (1–5 μM vs 20–30 μM). These appear to be the first Ku70/80 small molecule inhibitors reported in the literature. For the peer review companion paper see Weterings et al. [28].Published: 23 February 2017WO/2017/031255Inhibitors of Rpn11Inventors: Li J, Cohen S, Perez C, Ma YApplicant: California Institute of Technology, Pasadena, CA, USAMeSH keywords: neoplasms • proteasome endopeptidase complexThe 19S regulatory system of the proteasome traps and unfolds polyubiquitinated proteins, which are then translocated into the active site of the 20S complex, and expelled as oligopeptides. Within this complex cycle of events it is the proteasome regulatory particle lid subunit Rpn11 (a zinc metalloisopeptidase) within the 19S complex that hydrolyzes the polyubiquitin bound to the protein and releases the ubiquitin into the cytoplasm to be recycled [29]. This ubiquitin recycling step is necessary for protein degradation to occur, and its inhibition is a target for proteasome inhibition and cell apoptosis. The catalytic JAB1/MPN/Mov34 metalloenzyme (JAMM) motif of Rpn11 is found in seven different human proteins including the Csn5 subunit of the COP9 signalosome, AMSH, AMSH-LP, the BRCC36 subunit of BRISC, MPND and MYSM1 [30]. The candidate Rpn11 inhibiting compounds of the present invention were developed from an original screening of a metal binding pharmacophores library as described in WO/2012/158435 (Cleave Biosciences, Inc.), which yielded a highly potent fragment, 8-thioquinoline (8TQ); however, compounds with this moiety exhibited no selectivity toward other enzymes containing the JAMM motive. The molecules of the present invention retain the 8TQ moiety, inhibiting Rpn11 with IC50 values of 1 μM or less, but inhibiting Csn5 and/or AMSH with an IC50 of above 1 μM (typically, differing by an order of magnitude). SAR studies of 2-carboxyl-8TQ polar derivatives demonstrated that functionalization at the 2-position was not well tolerated. For the peer review companion paper see Perez et al. [31].Published: 23 February 2017WO/2017/033951Novel analgesicInventors: Arai I, Takeda H, Tsuji M et al.Applicants: International University of Health and Welfare, Tochigi, JapanMeSH keywords: analgesia • interleukinsIL-31, an inflammatory cytokine mostly produced by type-2 T-helper cells [32], has mostly attracted attention for its involvement in pruritus and atopic dermatitis [33]. However, most recently it has been reported to promote growth of sensory nerves [34], and it is known that immune cells (e.g., mast cells) can directly communicate with sensory nerves during inflammation and pruritus via histamine, tryptase, prostanoids or peptides [35]. In apparent contradiction, the inventors report that recombinant IL-31, or IL-31 agonists (unspecified), act as analgesics, or can at least potentiate the action of known analgesics, as was shown in the mouse hot plate paradigm in combination with morphine, loxoprofen or capsaicin. Recombinant IL-31 (50 μg/kg i.p.) was also able to completely inhibit development of morphine tolerance in mouse models.Published: 2 March 2017WO/2017/035438Compositions and methods for drug sensitization of parasitesInventors: Reddy MCM, Sacchettini JC, Valluru SApplicant: The Texas A&M University System, TAMU College Station, TX, USAMeSH keywords: acetyl-CoA carboxylase • herbicides • protozoan infectionsMany parasites are completely or highly resistant to available drugs and drug combinations, and their re-sensitization to xenobiotics has always been a challenge for pharmacotherapy. In cases where the resistance stems from increased activity of the P-glycoprotein (Pgp)-linked drug efflux pump, combined calcium channel and Pgp blockers such as the R(+) form of verapamil have been employed with some success [36,37]. The inventors claim to have a new solution: using arylphenoxypropionate herbicides (quizalofop, fenoxaprop, haloxyfop, and their variants) that interfere with the parasites' lipid synthesis by inhibiting acetyl-CoA carboxylase, the enzyme which provides malonyl-CoA for the biosynthesis of fatty acids. The inventors have focused their experiments on Cryptosporidium parvum infection of cultured HCT-8 cells (an ileocecal colorectal adenocarcinoma cell line). Quantitative Reverse Transcription-PCR (qRT-PCR) was used to quantify parasite 18S rRNA and the MIC50 was determined. In general, compounds with a benzothiazole core inhibited Cryptosporidium better than those with a benzopyrazine core; benzothiazole cores substituted with 6-Cl were more effective than benzothiazole cores with a 6-F or 5,6-di-F substitution; and α-methyl substitution at phenyl acetic amides improved inhibition as compared with unsubstituted phenyl acetic amides, often decreasing MIC50 to less than 100 nM. In the C. parvum-infected IL-12 knockout mouse model that resembles acute human cryptosporidiosis, NZ-366 (50 mg/kg) and NZ-369 (100 mg/kg) were more effective than paromomycin when administered after a single dose, and as effective as paromomycin over the course of the study. In a trial with C. parvum-infected newborn calves, NZ-369 (8.5 mg/kg p.o. every 12 h for 5 days) reduced fecal volume increase and weight loss relative to controls. In the broiler chicken model of coccidiosis, 20 mg/kg/day, duodenal lesion scores were reduced. Growth inhibition of Toxoplasma gondii and Trypanosoma brucei, correlating with inhibition of acetyl-CoA carboxylase, has been reported before for herbicides of this class [38,39]. The effects of these compounds in mammals, which may be due to the inhibition of acetyl-CoA carboxylase by their acyl-CoA derivatives [40], were not observed in the inventors' brief toxicity study, at concentrations twice as high as the effective ones. Synergy of these compounds with established drugs should allow further dose reduction.Published: 2 March 2017WO/2017/036811MiRNAs for the treatment of heart diseasesInventors: De Windt LJ, Dirkx E, Giacca MApplicants: Universiteit Maastricht, Maastricht, The Netherlands; Academisch Tiekenhuis Maastricht, Maastricht, The NetherlandsMeSH keywords: genetic therapy • heart failure • heart muscle cells • miRNAsThe invention provides miRNAs 106b, 93, and 25 that induce cell cycle proliferation of cardiomyocytes, promoting cardiac regeneration in heart diseases. The intronic miR-106b∼25 miRNA cluster, which displays high expression in early stages after birth and low expression in the adult heart, is located within the human minichromosome maintenance deficient 7 (MCM7) gene on chromosome 5. This extends the range of miRNAs that have been clearly implicated in cardiomyocyte proliferation – miR-1, 133 [41,42], 199a, 590 [43] and members of the miR-15 family [44]; some of which have an inhibitory action. Having shown that about 30% of cultured neonatal rat cardiomyocytes could be stimulated to re-enter the cell cycle by transfection with either of the three miRNAs (vs 10% in controls), the inventors randomized mice to receive coronary artery ligation to induce myocardial infarction, or sham surgery. Immediately after the infarct, animals received either a AAV9-based gene therapy vector construct designed to overexpress the miRNA-106b∼25 cluster members, or an empty AAV9 vector. (AAV9 has an intrinsic tropism for the myocardium, facilitating heart-specific delivery.) Sirius Red staining of myocardial cross sections just below the ligation site indicated that myocardial integrity was much better preserved, left ventricular mass was increased and the infarct was much smaller, in mice receiving gene therapy with the miR-106b∼25 cluster. Functionally, left ventricular posterior wall thickness, left ventricular internal diameter, and left ventricular ejection fraction were significantly preserved over time in the infarcted mice injected with AAV9–106b∼25. The miRNA 106∼25 cluster has also been implicated in gastric cancer [45].Published: 9 March 2017WO/2017/044807Reduction of ER-MAM localized APP-C99 and methods of treating Alzheimer's diseaseInventors: Schon EA, Area-Gomez EApplicant: The Trustees of Columbia University in the City of New York, NY, USAMeSH keywords: Alzheimer disease • amyloid beta-protein precursor • membrane microdomainsThis document, which traces back to a US provisional application of September 2015, attempts to exploit measures that correct the consequences of altered cholesterol and sphingolipid homeostasis in Alzheimer's disease (AD), which compromises neuronal cell membranes. Cholesterol esterification by ACAT1 (the source of the cholesteryl esters that are deposited in lipid droplets that accumulate in AD) enhances β-amyloid production; de novo ceramide synthesis and activity of sphingomyelinase, which converts sphingomyelin to ceramide, are upregulated. This is a consequence of sterol and sphingolipid levels being co-regulated in the cell. Mitochondria-associated endoplasmic reticulum membranes (MAM-ERs) are particularly rich in cholesterol and sphingolipids, giving it the properties of a lipid raft in which presenilin-1 and γ-secretase activity might reside, constituting an early, and critical, event in the pathogenesis of AD. Together with findings suggesting that impaired contact between MAM and mitochondria might underlie the pathology of several human neurodegenerative diseases [46], this is the groundwork for the inventors' recently published 'MAM hypothesis' [47,48]. To correct the imbalance, the level of MAM-ER-localized APP-C99 (the cholesterol-binding C-terminal fragment of the amyloid precursor protein) should be reduced. Among the named approaches are: increasing MAM-ER γ-secretase or presenilin-2 activity; inhibiting BACE1; increasing efflux, oxidation or esterification of cholesterol; administering an LDL receptor inhibitor; increasing phosphorylation of APP at Thr668; inhibiting endosome-to-MAM movement; and many more. Correspondingly, the number of theoretically suitable agents is in the hundreds; examples include the synthetic corticotrophin releasing factor, Xerecept® (developed by Celtic Pharma Holdings, Hamilton, Bermuda), the CRH-1 receptor blocker, Verucerfont (GSK-561,679); ERK and MEK inhibitors; and the monoterpene, auraptene (7-geranyloxycoumarin). Extensive experiments were carried out in immortalized neuronal cells and in cultured primary mouse cortical neurons, and the results are presented in 33 figures.Published: 16 March 2017WO/2017/045691Vaccine compositions comprising C-C motif chemokine 22 (CCL22) or fragments thereofInventor: Andersen MHApplicant: Herlev Hospital, Herlev, DenmarkMeSH keywords: cancer vaccines • chemokine CCL22 • tumor escapeThe thymus and activation-regulated chemokine CCL17, and the macrophage-derived CCL22, are agonists at the CCR4 receptor, which is known to promote tumor growth and metastasis; this axis is considered a therapeutic target in several types of cancer. CCL22 is a potent and rapid inducer of CCR4 internalization on human Th2 cells, while CCL17 is not [49]. Most importantly, CCL22 induces tumor immune tolerance via the CCR4 receptor, through recruitment of regulatory T cells and myeloid-derived suppressor cells into the tumor stroma [50]. Expression of CCL22 has been previously shown to cause accumulation of Foxp3+ regulatory T cells in ovarian, prostate, esophageal, gastric and breast carcinomas. The invention relates to a cancer vaccine based on CCL22 or derived peptides that targets and kills CCL22-expressing tumor cells. Interestingly, specific cytotoxic immune responses against CCL22 expressing cells can be raised even though such cells may antagonize the desired effects of other immunotherapeutic approaches. This activity is readily determined by subjecting peripheral lymphocytes, mononuclear cells, antigen-presenting cells or tumor cells from an individual to an enzyme-linked immunosorbent spot (ELISPOT) assay. The preferred embodiments use antigens of 8–11 amino acids length, derived from the human CCL22. Interestingly, all antigenically high-scoring epitopes were located in the signal peptide portion of the human CCL22 sequence (MDRLQTALLVVLVLLAVALQAT), which is cleaved off before the protein is secreted. One of the high-scoring peptides was RLQTALLVVL. When this CCL22-derived antigen or an HIV control peptide was used to stimulate peripheral blood mononuclear cells from 11 healthy donors and 13 cancer patients for one week, the CCL22 concentration in the culture supernatants from healthy donors significantly decreased following stimulation with the vaccine antigen (p = 0.02) while the decrease in supernatants from cancer patient-derived cells with high CCL22 expression (≥5000 pg/ml) had even higher significance (p = 0.005); however, the low-expression patients showed no significant response.Published: 23 March 2017WO/2017/046255Mono- or di-substituted indole derivatives as Dengue viral replication inhibitorsInventors: Kesteleyn BRR, Raboisson PJ-MB, Bonfanti J-F, Jonckers THM, Bardiot DAM-E, Marchand ADMApplicants: Janssen Pharmaceuticals, Inc., Titusville, NJ, USA; Katholieke Universiteit Leuven, Leuven, BelgiumMeSH keywords: antiviral agents • Dengue virusThe launch of the first Dengue vaccine, and promising results with additional candidates, has not made the development of therapeutic (and prophylactic) drugs less urgent. The present invention provides compounds which have been shown to possess potent antiviral activity against all four currently known virus serotypes. They were tested in Vero cells infected with DENV-1 strain TC974#666 (NCPV), DENV-2 strain 16681, DENV-3 strain H87 (NCPV) or DENV-4 strains H241 (NCPV) and EDEN (SG/06K2270DK1/2005). The compounds continue recently published work from CISTIM Leuven vzw (Leuven, Belgium) on Dengue and yellow fever virus replication inhibitors with a central imidazole moiety [51]. The best of these earlier compounds had EC50 values of 0.5 μM, at least 235-fold lower than the respective cytotoxic concentration. The compounds from this invention improve vastly on this, most having EC50 values in the picomolar range and selectivity indices better than 10,000 against Dengue serotypes 1 and 2, and low-nanomolar EC50 values with selectivity indices around 1000 for serotypes 3 and 4. Their molecular mechanism is not disclosed. An exemplary compound of the invention is 2-(4-chloro-2-(2-hydroxyethoxy)phenyl)-1-(6-fluoro-1H-indol-3-yl)-2-((3-methoxy-5-(methylsulfonyl)phenyl)amino)ethanone.Published: 23 March 2017WO/2017/053842Methods for the treatment of epilepsyInventor: Rajan SApplicants: Genentech, Inc., South San Francisco, CA, USA; F. Hoffmann-LaRoche AG, Basel, SwitzerlandMeSH keywords: epilepsy • fibroblast growth factors • KLB protein • humanAmong the unique challenges of epilepsy is the fact that no single drug reliably prevents seizures in more than half of the patients. Ketogenic diet is about as effective (i.e., as drug therapy) because it also prevents seizures in about half of the affected children [52]. One feature of such high-fat, adequate-protein, very low-carbohydrate diets is that they increase levels of circulating FGF-21 [53], an important metabolic regulator. Most recently it has been shown that the known neuroprotective and life-extending effects of long-term caloric restriction, and the recently reported neuroprotective and mood-stabilizing effects of FGF-21 [54], might be linked through the AMPK/mTOR pathway [55]. At the September 2015 priority date, the inventors' claims that activation of FGF-21 receptors by any conceivable means (including action at the receptor cofactor, membrane-spanning βKlotho) can treat seizures and epilepsy was at the cutting edge of research. Normal mice in the maximal electroshock seizure or corneal kindling models were protected (partially and fully, resp.) by weekly i.p. doses of 1 and 3 mg/kg (but not 0.5 mg/kg) of the anti-FGFR1c monoclonal antibody R1MAb1 (described in WO/2012/158704), which activates the FGF-21 receptor [56]. Most likely, Amgen's βKlotho binding monoclonal antibody mimAb1, which specifically activates signaling from the βKlotho/FGFR1c receptor complex [57], would have similar activity.Published: 30 March 2017Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Boomsma F, Hut H, Bagghoe U, van der Houwen A, van den Meiracker A. Semicarbazide-sensitive amine oxidase (SSAO): from cell to circulation. Med. Sci. Monit. 11(4), 15795708 (2005).Google Scholar2 Mercier N, Osborne-Pellegrin M, El Hadri K et al. Carotid arterial stiffness, elastic fibre network and vasoreactivity in semicarbazi
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