So much output from the WIPO and so little time to review! – But here are some more applications published in September and early October 2013. Stay tuned!
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More on Antiangiogenic Itraconazole
The antiangiogenic potential of the popular antifungal drug itraconazole(Sporanox®) was reported over six years ago (ACS Chem Biol. 2007; 2(4):263-70, here). It has been in clinical trials for prostate cancer (Oncologist2013;18(2):163-73, here) and non-small cell lung cancer (Cancer Res. 2011; 71(21):6764-72, here), with modest success. Filing WO/2013/155218(Johns Hopkins Univ. [US]; Oct. 17, 2013) still made sense because the claims are for chirally pure isomers of the molecule, which contains three stereocenters. All eight stereoisomers were synthesized and evaluated for activity against human vascular endothelial cell (HUVEC) proliferation and for antifungal activity against five strains. The 4R-cis diastereomer (IC50= 0.056 ± 0.01 μΜ) was found to be about 20-fold more potent as an anti-angiogenic than the 4S-cis form (IC50 = 1.1 ± 0.13 μΜ). Interestingly, the inhibition of endothelial cell cycle by itraconazole may be mediated at least in part through the inhibition of sterol 14α-demethylase, which is also responsible for the antifungal activity. Unlike HUVEC inhibition, the sensitivity of fungal growth to itraconazole is dictated not by cis-transconfiguration of the dioxolane ring but instead by the absolute stereochemistry at the 2 and 4 carbonatoms.
Maprotiline, Venlafaxine, and Phenobarbital for Bradycardia
WO/2013/154408(Univ. Rabat [MA]; Oct. 17, 2013) – the first patent application from Morocco that we are listing here – claims a new application for maprotiline. In a daily dose of 25 to 75 mg, the anticholinergic and tachycardic effect of this old tricycic antidepressant is exploited to reduce the exaggerated vagal response in the treatment of autonomic dysregulation. The focus is on symptomatic dysautonomic bradycardia subsequent either to vagal hyperactivity or to sympathetic deficiency, which is diagnosed through stimulation tests. In WO/2013/154409the same claims are made for venlafaxine, a much more selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that Pfizer had launched as Effexor and which went off patent recently. Here the effect on alpha and beta adrenergic receptors is exploited, with once-daily dose is 37.5 to 70 mg. WO/2013/154410names phenobarbital, at a dose of 0.5 to 1 mg/kg per day, for hypertension. The claims include preventive treatment of persons with a genetic predisposition to primary arterial hypertension with heightened sympathetic response.
5-HT1A Receptor Agonists for Hypercholesterinemia
It has been reported that cholesterol levels beyond 200 mg/dL reduce the response rate to selective serotonin reuptake inhibitor antidepressants (Psychosomatics 2002; 43:310-6, here); on the other hand, fluoxetine and sertraline elevate cholesterol levels (e.g., CNS Drugs 2009; 23:857-65, here). Inventors of WO/2013/152108(Individuals [US]; Oct. 10, 2013) have now found that 5-HT1A agonists (which are not known to inhibit HMG-CoA reductase, nor do they have chemical structures that are similar to statins) reduce cholesterol levels. Gepirone, ipsapirone, tandospirone, adatanserin, flesinoxanand buspironeare specifically mentioned, at doses from 20-80 mg per day. – In this context it is interesting to know that the 5-HT1A receptor has cholesterol binding sites (J Phys Chem B. 2012;116(43):12991-6, here) and that sterols can alter the dipole potential in hippocampal membranes in ways that affect the function of this receptor (Biochim Biophys Acta 2013; 1828(3):917-23, here).
Mepenzolate for COPD
Mepenzolatebromide is an old muscarinic receptor antagonist that remains in limited use to treat gastrointestinal disorders, such as peptic ulcers and irritable bowel syndrome. That this type of pharmacological activity is useful for treating obstructive pulmonary disease is an old story (see the paper on the GLOW study program for glycopyrrolate, reported in Curr Med Res Opin. 2013 Nov 19, here) but apparently it has not been reported for this particular compound — which WO/2013/137009(LTT Bio-Pharma [JP]; Sept. 19, 2013) has now corrected. The companion peer review paper is Nat Commun. 2013 Nov 5; 4, here. – Mepenzolate was among the muscarinic blockers investigated for form-deprivation myopia in Invest Ophthalmol Vis Sci. 2003; 44(3):1330-8 (here)
Rho Kinase Inhibitors for ALS
Fasudilis an inhibitor of Rho-associated kinase (ROCK) II IC50 1.9 µM) that was launched in Japan in 1995 to treat cerebral vasospasm following surgery for subarachnoid hemorrhage and associated cerebral ischemic symptoms. It is the only ROCK inhibitor licensed for clinical use. Considering the deep involvement of ROCK in apoptosis, such compounds have been examined for their potential to treat chronic forms of neurodegeneration, including those affecting the motor system. In 2011 the Michael J. Fox Foundation sponsored investigations concerning Parkinson’s disease, and beneficial effects on models of multiple sclerosis have been reported for several years (J Neuroimmunol. 2006; 180(1-2):126-34, here). WO/2013/135596(Univ. Göttingen [DE]; Sept. 19, 2013) extends this to amyotrophic lateral sclerosis, claiming fasudil and its active metabolite, hydroxyfasudil. A competing group at Gifu Pharmaceutical University has published similar findings almost simultaneously with this patent application (Br J Pharmacol. 2013; 170(2):341-51, here).
PPAR Agonists for Respiratory Infections
After a wrong-footed start as diabetes drugs, peroxisome proliferator activator receptor (PPAR) agonists have become popular candidates for drug repurposing, with Senju claiming them for dry eye in WO/2007/061094, the Rhode Island Hospital making claims for alcohol-induced brain damage in WO/2008/030604, and Takeda advancing pioglitazoneinto a Phase III clinical program for Alzheimer’s disease with its partner Zinfandel Pharmaceuticals — just to give a few examples. WO/2013/134626(Harvard Univ. [US]; Sept. 12, 2013) goes for respiratory infections, “based on inventor’s discovery that PPARδ and/or PPARγ enhance bacterial killing activity of myeloid cells, such as macrophages and neutrophils. The killing activity is enhanced against both gram-negative and gram-negative species. Without wishing to be bound by a theory, it is believed that PPARδ and/or PPARγsimply improves phagosome activity by regulating the expression of phagosome proteins.” Pretty much all compounds with this type of activity are claimed: the glitazones, farglitazar, fenofibrate, and experimental compounds such as pirinxic acid, L-165041, L-796449, L-165461, L-16504, GW-0742, GW-2433, GSK-677954, and Endurobol, a PPARδ agonist that seems to be preferred. It was used for data generation in a mouse model of pneumonia and in bacterial killing assays.