A variety of international patent applications have crossed our desks during the past three weeks, and here we present four examples: bupropion for SSRI-induced sexual female dysfunction; 11beta-HSD1 inhibitors for neuropathy; N-acetylcysteine for anxiety disorders; and a successful concerted repurposing effort to identify approved drugs that could be used to treat hookworm infection. – If you want to know more about our patent-supported drug repurposing knowledgebase, please contact us at office@hmpharmacon.com.
Bupropion Repurposed, Again
GlaxoSmithKline’s bupropion((±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one) started out as a mainly dopaminergic and noradrenergic anti-depressant (Wellbutrin), but as its side effect profile at the effective dose includes a propensity for causing seizures and cardiovascular problems it never took full hold on the market – although avorable reports continue to be published (e.g., here). Its second life at GSK, with very limited economic success (sales $9.7 million in 2009) was as a smoking cessation aid (Zyban); generics are already available. Another attempt was made by Orexigen Therapeutics, which combined bupropion with naltrexone to treat obesity; the FDA demanded a cardiovascular safety trial which is now ongoing. Most recently the scientific literature has been rife with reports of promise for bupropion in yet another application: reversal of SSRI-induced sexual dysfunction, especially in women (see e.g., here). WO/2012/028834(Individual inventors [NL/BE]; March 8, 2012) brings these insights into patent format. Both inventors are from academia.
11β-HSD1 Inhibitors for Neuropathic Pain
11beta hydroxysteroid dehydrogenase 1 (11β-HSD1) regenerates active glucocorticoids from their inactive 11-keto derivatives (e.g., cortisone to cortisol) in a NADPH dependent manner and is widely expressed not only in the liver but also throughout the adult CNS. Psychiatric effects of 11β-HSD1 are known, mostly in the context of glucocorticoid programming, and Abbott Laboratories’ WO/2011/068927had already claimed inhibitors of 11β-HSD1 for inflammatory pain. WO/2012/033070(Astellas [JP]; March 15, 2012) demonstrates that triazole inhibitors of 11β-HSD1, especially those with a ring group at the 3- or 5-position, all of which are known from earlier patenting, are also effective in purely neuropathic pain. This is non-trivial, and actually quite difficult to explain; the literature does not suggest mechanisms.
Still Something New for N-Acetylcysteine?
At first sight it is difficult to imagine that a nutritional supplement such as N-acetylcysteine (which however has well-established drug uses as a mucolytic and nephroprotective agent) could still offer surprises. In fact there are dozens of repurposing possibilities documented in the literature. WO/2012/033235(Sun R&DB Foundation [KR]; March 15, 2012) adds claims for treating anxiety disorder such as posttraumatic stress disorder or phobia. Getting this patent application granted is not going to be easy: there are many precedences. N-acetylcysteine has been reported as being effective in trichotillomania(hair pulling; see here) and onychophagia(nail biting; see here), both anxiety-related disorders from the range of obsessive-compulsive conditions that are considered to be closed linked to PSD. The current literature regarding the use of N-acetylcysteine in disorders including addiction, compulsive and grooming disorders, schizophrenia and bipolar disorder has recently been reviewed.
Surprising Perspectives for Hookworm Disease
Hookworm disease affects up to 600 million people worldwide, virtually all of whom live in resource-limited countries. Vaccination with recombinant Ancylostoma ceylanicum macrophage migration inhibitory factor (AceMIF) provides partial protection from disease. In WO/2012/033878(Yale Univ. [US]; March 15, 2012) the inventors subjected almost 1,000 FDA-approved drugs and other bioactive compounds to a high-throughput screen for dopachrome-methyl ester tautomerase activity of AceMIF. Compounds that showed >60% inhibition were subjected to a more comprehensive analysis. Sodium meclofenamate(a non-steroidal anti-inflammatory drug), furosemide(a diuretic used to treat hypertension and heart failure), hydroxyzinepamoate (an anxiolytic) and cobalaminewere found to inhibit AceMIF as required. Furosemide, hyroxyzine and cobalamine had substantial antihelminthic activity with 40-50% worm-killing effect. Meclofenamate, the most potent enzymatic inhibitor, had worm killing activity of 0-15%, indicating that the blocking the AceMIF active site is insufficient to kill hookworms ex vivo. Furosemide exhibited the best combination of inhibitory activities: it had sub-micromolar binding to the AceMIF active site) and IC50 for CD74 receptor binding, IC50 of 1 μΜ in monocyte chemotaxis experiments, and the highest potency in the worm-killing assay. However, its strong diuretic activity makes it unsuitable as an antihelminthic, at least for human use. For the companion paper see here.