And a very good day to you, colleagues in drug repurposing! Shame on us for not posting for many weeks, but this kind of activity is contingent on free time slots – which were just not available for most of the time. Drug repurposing activities have not taken a break though. OK, here we go with five applications published in August.
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Identifying Repurposing Candidates for Graft Rejection
In spite of the numerous claims for new uses for known drugs there are actually very few patent applications claiming methods for identifying such repurposing opportunities — which is why we put WO/2013/112933(Lleland Stanford Univ. [US]; Aug. 1, 2013) upfront here. The document focuses on allograft rejection, changes in gene expression patterns induced by this condition, and modulators of these changes. The focus is on tyrosine kinase inhibitors (e.g., BCR/ABL and Src families), HMG-CoA reductase inhibitors, and antibodies that selectively bind to a common acute graft response factor (e.g., CXCL10– also known as interferon-γ-inducible 10-kd protein, IP-10). Dose-response curves derived from cell cultures or animal models of allograft rejection were used for computation. A generic “common rejection module” consisting of 11 genes that were significantly overexpressed during biopsy-confirmed acute rejection was identified through microarray profiling, and then validated in 503 human renal transplant biopsies. In specific embodiments, the Src family tyrosine kinase inhibitor is dasatinib(Bristol Myers’ Sprycel); the statin is atorvastatin(Lipitor and generics); and the antibody is MDX-1100, a fully human anti-CXCL10 mAb that Medarex had investigated for ulcerative colitis and rheumatoid arthritis (Arthritis Rheum. 2012; 64(6):1730-9, here) before the company was acquired by Bristol-Myers Squibb in 2009. Dasatinib and atorvastatin were tested in a murine FVB-to-C57BL/6 heterotopic cardiac transplant model, with cyclosporine as a positive control. Atorvastatin affected monocyte- and macrophage-related pathways, while dasatinib modulated cell cycle-related pathways.
Reducing Vitamin E Levels to Treat Malaria
One well-known – but very unspecific – approach to treat or prevent malaria is to reduce intracellular alpha-tocopherol levels; this is part of the antimalarial action of chloroquine, an agent known for its function of elevating the pH in acidic compartments (Genes Cells 2003; 8(10):789-800, here). WO/2013/118606(Natl. Inst. of Advanced Industrial Science [JP]; Aug. 15, 2013)presents three additional compounds that achieve this: probucol, an anti-hyperlipidemic, antioxidant, and anti-inflammatory drug initially developed for coronary artery disease but now with many experimental uses; ezetimibe(Merck & Co.’s Zetia), a transport inhibitor for cholesterol and other highly hydrophobic compounds (such as tocopherol); and cyclosporin A which has long been known for its antimalarial activity – however, not in the context of vitamin E uptake. The new context is that CsA inhibits ABCA1-mediated lipid efflux (Arterioscler Thromb Vasc Biol. 2004; 24(11):2155-61, here).
Sartans for Insomnia
Peripheral angiotensin-II is pivotal in arterial hypertonia, but central angiotensin-II and AT1 receptor expression increase during psychological stress and, in turn, activate both the neuroendocrine and sympathoadrenal systems in the brain, giving the angiotensin system an important role in stress responses (Pharmacol Res. 2013; 76:49-5, here). The claims in WO/2013/119605(Univ.of Pittsburgh [US]; Aug. 15, 2013) are based on the results of experiments performed in a validated rat model of stress-induced insomnia in which candesartanand Takeda’s azilsartan(antagonist and inverse agonist at AT1 receptors, resp.) were found to ameliorate stress-induced sleep disturbances. The effect of azilsartan seemed to last longer: rats showed 20% more sleep in the last two hours of the experiment (4 hours after injection of the drug) compared to candesartan-treated rats — in good correlation with the longer-lasting effect of azilsartan in humans treated for hypertension.
A Fistful of Drugs for Pre-Alzheimer
WO/2013/123426(Buck Institute [US]; Aug. 22, 2013) specifically claims four known drugs to treat so-called preclinical Alzheimer’s disease (the recently defined prodromal condition without even mild cognitive impairment): the antiemetic 5-HT3 receptor antagonist and partial alpha7-nicotinic receptor agonist tropisetron(marketed by Novartis in Asian markets as Navoban), disulfiram(Antabuse, the original drug to prevent alcohol abuse), the biphenol honokiol(an antidepressant and antithrombotic), and the sedating benzodiazepine nimetazepam. There does not seem to be prior art precedence for disulfiram and nimetazepam, but the use of “setrons” in Alzheimer’s was investigated in the 1990s (Methods Find Exp Clin Pharmacol.1998; 20(8):725-33, here), and Alzheimer claims for honokiol would seem to be preempted by Phytother Res. 2010; 24(10):1538-42 (here). However, the inventors’ finding is that these drug promote processing of amyloid precursor protein by the (non-pathological) non-amyloidogenic pathway, preventing the formation of neurotoxic amyloid oligomers and plaques. Data from Abeta-overexpressing PDAPP mice support the positive cell culture results for tropisetron and nimetazepam in vivo. Disulfiram has low blood-brain-barrier penetration (brain/plasma ratio <0 .1="" and="" at="" being="" bond.="" brain="" degrades="" disulfide="" font="" in="" probably="" rapidly="" reduced="" the="" tissue="">
Calcineurin Inhibitors for Lesional Vestibular Disorders
Lesions of inner ear cells and/or the vestibular nerve, and disorders that affect the inner ear endolymph (such as Meniere’s disease) cause vertigo and compromise motor balance which can lead to falls, especially in the elderly. WO/2013/124416(INSERM [FR]; Aug. 29, 2013) claims, on the basis of animal model results, that calcineurin inhibitors can counteract this — not very surprising because their neuroprotective effect (caused by calcium influx blockade) is known; not only in general but also for acoustic trauma (Hear Res. 2005; 209(1-2):86-9; here). The list of compounds is long and includes cyclosporin A, voclosporin (Isotechnika / Lux Biosciences’ Luveniq, a failed candidate for noninfectious uveitis), tacrolimus (many brands), 4-(fluoromethyl)phenyl phosphate, tyrphostins, norcantharidin, okadaic acid, kaempferol, barbiturates, gossypol, dibefurin (Abbott; J Antibiot (Tokyo) 1996; 49(2):124-8; here), dipyridamole (Persantine), trifluoroperazine, caffeic acid phenyl ethyl ester, and their derivatives — to name only the small molecules.