Again, clever inventors have proven ingenious and busy in filing international patent applications that claim new (and sometimes surprising) uses for abandoned, marketed, or in-development drugs – and again H.M. Pharma Consultancy has selected five examples (published between May 10 and May 24, 2012) for brief discussions: tarenflubil for multiple sclerosis; lisuride and tergolide for fibrosis; alaremycin for malaria; memantine and tromantadine for cancer; and aldose reductase inhibitors for periodontitis. – If you wish to know more about our intellectual property and drug repurposing services, please peruse this blog, visit our website, or contact us at office@hmpharmacon.com .
Yet Another Use for R-Flurbiprofen
Tarenflurbil(MPC-7869, Flurizan), the R-isomer of flurbiprofen, has hardly any effect on cyclooxygenase enzymes, COX-1 and COX-2 inhibition resides almost exclusively in the S-enantiomer of the racemate. However, it has several other interesting pharmacological features, such as selective inhibition of gamma secretase and induction of the p75(NTR) protein which is beneficial in several solid tumors including prostate carcinoma (Cancer Res. 2007; 67(7):3254-62 PubMed). Myriad Pharmaceutical’s clinical program for Alzheimers’ disease failed the efficacy endpoint (JAMA 2009; 302(23): 2557-64 PubMed), the status of Myrexis Inc.’s Phase II trial for delaying the recurrence of localized prostate cancer (NCT00045123) is unclear, and so is Horizon Pharma Inc.’s investigation for tarenflurbil in neuropathic pain. WO/2012/059541(J. W. von Goethe University [DE]; May 10, 2012) makes another jab, this time for multiple sclerosis. In the standard experimental autoimmune encephalomyelitis (EAE) C57BL6 mouse model of MS, 9 mg/kg/d p.o. prevented EAE completely when therapy was started on day 1 and animals had significantly reduced EAE scores and optic neuritis damage when treatment was started 5 or 8 days after the trigger injection (MOG35-55 peptide and pertussis toxin). Many additional data are presented that strengthen these findings.
Ergolines for Organ Fibrosis
The two 8-alpha ergolines, lisurideand terguride(trans-dihydrolisuride) are mixed dopamine receptor partial agonists and 5-HT2 receptor antagonists with a long and varied history. While both had been (and still are) used for Parkinson’s disease and/or hyperprolactinemia in some countries, terguride is under investigation for pulmonary arterial hypertension by Sinoxa Pharma of Berlin under orphan disease regulations. WO/2012/062676(Sinoxa Pharma [DE]; May 18, 2012), filed at the time of the regular publication (but months after the epub-ahead-of-print) of a paper describing the positive effects of terguride in idiopathic pulmonary fibrosis (Thorax 2010; 65(11): 949-55 PubMed), claims the use of both drugs for the slowing or reversal of fibrotic organ remodelling caused by mesenchymal proliferation and life extension in fibrotic diseases. At least 90% of 5-HT2A/B receptor occupation is required as long as symptoms exist. Note that other ergolides with agonist action of 5-HT2B receptors, such as pergolide, have been associated with fibrotic cardiac valvulopathy.
An Antibiotic for Malaria
Alaremycin (5-acetamido-4-oxo-5-hexenoic acid; Biosci Biotechnol Biochem. 2005; 69(9):1721-5 PubMed) closely resembles 5-aminolevulinic acid, the substrate of porphobilinogen synthase, and is an efficient inhibitor of this heme biosynthesis pathway enzyme. It is an effective antibiotic against Pseudomonas ssp. Inventors of WO/2012/063487(Tokyo Institute of Technology [JP]; May 18, 2012) have surprisingly found that it is also effective against Plasmodium falciparum, inhibiting the parasite’s nucleic acid metabolism and protein synthesis in erythrocytes in a concentration-dependent manner. The scientific rationale is not easy to make out for us from the machine translation but might be related to the fact that alaremycin could also inhibit delta-aminolevulinic acid dehydratase, which catalyses the second reaction in the heme biosynthetic pathway and is encoded by the malaria parasite (Curr Genet. 2002; 40(6): 391-8 PubMed). – Alaremycin is a simple molecule, and easily synthesized (see here) but does not yet seem to have entered clinical development; this patent application from its discoverer is not so much repurposing but an early use extension in a somewhat unexpected direction.
Adamantanes for Cancer
WO/2012/065383and WO/2012/065384(Lialong Lifeng Scientific & Development and South China Center for Innovative Pharmaceuticals [CN]; May 24, 2012) claim memantine(‘383), a well-selling drug for Alzheimer’s disease, and the antiviral tromantadine(‘384) for a broad range of solid tumors. While both are based on the adamantane structure and are marketed (inter alia) by Merz+Co (as Axura/Akatinol and Viru-Merz, respectively), they share few if any pharmacological properties: memantine is an NMDA open-channel antagonist while tromantadine inhibits a late step in herpes simplex virus type 1 replication and syncytium formation. The compounds were tested on the human colon cancer cell line HT-29, the human pancreatic cancer cell line Panc-1, NCI-H460 human lung cancer cells, and others. Since it was demonstrated that active NMDA receptors are expressed by most breast cancers and influence their survival (Breast Cancer Res Treat. 2010; 122(2):307-14 PubMed), publication activity on the potential utility of adamantanes in cancer has taken off, and the November 2010 Chinese priority date of these two patent application fits in well.
Aldose Reductase Inhibitors for Periodontitis
Periodontitis, the ingrowth of bacterial plaque into the gum anchorage area of the teeth, is the single most significant cause of tooth loss, and the most frequent chronic disease of man. Poorly controlled diabetes mellitus exacerbates the condition. WO/2012/067614(Individual [US]; May 24, 2012) revives an ill-fated class of drugs for diabetic complications, aldose reductase inhibitors (ARIs), for this purpose. The application claims adding sorbinil, 2-methyl sorbinil, imirestat (about 12 mg/kg/day), tolrestat (about 20 mg/kg/day), ZD-5522, or the bioflavonoid quercetin (about 50 mg/kg/day) to the diet. Interestingly, the data show this therapy principle to work not only in streptotocinized diabetic rats, but also in non-diabetic ones. This seems to be due to the curbing of inflammatory responses downstream of aldose reductase. See two papers from the inventor, J Periodontol. 2011; 82(6): 926-33 (PubMed) and Postgrad Med. 2010; 122(3): 138-44 (PubMed). – ARIs have not been without safety problems in clinical trials for diabetic neuropathy and cataract, which is why their original Japanese developers (and later, Pfizer) mostly gave up on them. Topical applications, e.g. into the inflamed periodontal pocket, might offer a much better route of administration than dietary additions.