The repurposing community has been inordinately busy and creative during the months when the PCT disclosures that are now being rolled out were filed. In fact there are so many documents in our hold file right now that we are only doing about half the evaluations now — more is to follow in one or two batches later in August. Here’s what we are presenting today: cannabinoid receptor ligands for endometriosis; an old antidiabetic for hearing loss; the prostaglandin latanoprost, used to treat glaucoma, for bipolar disorder; and – probably strangest of all – sodium thiosulfate for obesity.
For your repurposing needs, please contact us at office@hmpharmacon.com .
Cannabinoid Receptor-2 Agonists for Endometriosis
One in ten of all women in their reproductive years suffer from endometriosis(the irregular extrauterine growth of tissue derived from uterus lining) to some degree. The involvement of the endocannabinoid system in cellular migration – a key step in the establishment of endometriosis – has been known for some time, and cannabinoids were once used to alleviate endometriosis-associated pain. CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis’s abnormal growths Pain 2010;151(3):703-1 PubMed), and a few weeks ago it was reported that expression of these receptors is disrupted in endometriosis (Fertil Steril. 2012; PubMed). WO/2012/098090(Bayer Pharma [DE]; July 26, 2012) lists more or less every known CB2 receptor agonist for the same purpose (and on this occasion gives a valuable tabulation of these compounds, complete with chemical structure and related patent application). The document focuses on two classes of benzofuranes and sulfonamides first claimed by Pharmos Corp. in WO/2006/129318and WO/2008/075353, resp., most specifically on rel-(5aR,9aR)-3-(1,1-dimethyl-heptyl)-7,7-dimethyl-5a,6,7,8,9,9a-hexahydro-dibenzo[b,d]furan-1-ol, and on RQ-00202730, a selective CB2 agonist under development for irritable bowel syndrome by the Japanese company RaQualia Pharma, Inc. In a Balb/c mouse model of endometriosis, 2 x 30 mg of the Pharmos compound (apparently a second-generation compound to Cannabinor [PRS-211,375]) were effective against growth of transplanted ectopic tissue.
Glibenclamide for Hearing Loss
Inhibitors of ATP-sensitive potassium channels are effective antidiabetics because their primary action causes beta cells to depolarize, which results in the opening of voltage-dependent calcium channels and ultimately, release of insulin. It has been reported that glibenclamide, the prototypic molecule of this class, has some potential as an antithrombotic because it also blocks platelet thromboxane A2 receptor receptors (Acta Pharmacol Sin. 2010; 31(2):150-9 [PubMed] and Eur J Pharmacol. 2010; 649(1-3):249-54 [PubMed]). WO/2012/098143(Univ. Frankfurt [DE]; July 26, 2012) stays with the original molecular target but switches to the inner ear as the new target organ. Wild-type C57BL/6 mice were implanted with subcutaneous pellets releasing glibenclamide (27.8 μg/day) over a period of up to 7 months, and showed a delayed onset of and significantly less age-related hearing loss compared to placebo-treated controls, especially at higher frequencies (at 22.6 kHz the threshold of the glibenclamide-treated group was about 15 dB below that of placebo-treated controls). A tenfold higher dose also afforded protection against hearing loss from acoustic trauma (8-16 kHz at a sound pressure level of 112 dB for 120 minutes).
Latanoprost for Bipolar Disorder
The very recent report (J Affect Disord. 2012;138(3):479-84 PubMed) disclosing that the gene coding for prostaglandin-D2-synthase is among those that are differentially expressed in bipolar disorder does not endanger the novelty of WO/2012/100347(Inceptum Res. & Ther. [CA]; August 2, 2012) which, in a nutshell, claims prostaglandin F2alpha analogs such as latanoprost(developed for glaucoma as Xalatan, now generically available) as glycogen synthase kinase-3 (GSK-3) inhibitors. Effectively, this assigns these compounds additional pharmacological profile elements relating them to of lithium and valproate. A huge amount of complex biological data is provided, much of it confocal microscopy visuals of Drosophila wing imaginal discs. More comes from HEK293T cell protein Western blots; the relative levels of 5HT2A receptors, TCF1/LEF1, BDNF, phosphorylated Serl33-CREB, CREB, and TNF-alpha in U87MG cells exposed to latanoprost (1, 5, or 10 μΜ) are also presented. Treatment of wing imaginal discs with1, 5, 10 or 20 μΜ of latanoprost, all resulted in a significant activation of the Distalless (DU) protein, and thus inhibition of GSK-3 activity in vivo compared to treatment with a DMSO control vehicle. Results of open field tests with mice treated with 40 mg/kg latanoprost or 200 mg/kg lithium are shown.
Sodium Thiosulfate for Obesity
The mitochondrial enzyme thiosulfate sulfurtransferase (rhodanese) is expressed from the TSTgene and detoxifies cyanide to thiocyanate. Nobody had associated it with obesity and related metabolic disorders, but this is what WO/2012/104589(Univ. Edinburgh [GB]; Aug. 8, 2012) has found: rhodanese was low in adipose tissue from a number of obese mouse strains and in fat from obese patients. Transgenic C57BL/6N mice that overexpressed rhodanase in adipose tissue were created, and found to be very lean. Snapshot microarray analysis carried out with or without a preceding glucose challenge revealed white adipose tissue-specific changes in gene expression, with the caveat that many gene pathways may be linked, or operate differently/reciprocally from white fat and non-adipose tissues. Rhodanese knockdown in adipocytes freshly differentiated from 3T3-L1 preadipocytes showed elevated lipid accumulation and less secretion of the insulin-sensitizing hormone adiponectin, which could be reversed by exposure to compounds such as sodium thiosulfate. The inventors explicitly suggest repurposing sodium thiosulfate, which is in clinical use for cyanide poisioning (J Appl Toxicol. 1999; 19(3):173-83 PubMed) and severe tissue calcium deposition (Semin Dial. 2010; 23(3):258-62 PubMed; Nephrol Dial Transplant. 2010; 25(6):l 923-9, see here), for obesity and type II diabetes.