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新药研发与药物合成

 
 
 

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Heavy Drugs  

2013-07-14 18:47:19|  分类: 药物化学 |  标签: |举报 |字号 订阅

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Biotech companies are making inroads in clinical trials and with the US Patent and Trademark Office (PTO) with deuterated versions of established pharmaceuticals. The deuterated analogues, in which one or more key carbon-hydrogen bonds are replaced with carbon-deuterium bonds, are demonstrating longer metabolism cycles, improved safety, and greater effectiveness than the pioneer drugs. Pre-clinical and clinical studies are underway in a broad range of therapeutic areas, among them infectious diseases, depressive disease disorders, chronic kidney disease, pulmonary arterial hypertension, cancer, rheumatoid arthritis, and HIV.

Deuterium is a non-radioactive version of hydrogen that contains a proton and a neutron, rather than just a proton. The addition of the neutron makes the "heavy" hydrogen isotope’s chemical bonds stronger and more stable, creating potentially beneficial properties, while maintaining identical chemical properties, including solubility, melting point, and target receptor protein binding.

For decades, biochemists have been using the "kinetic isotope effect" of deuterium to help determine enzyme reactions in metabolism studies. But, it is only recently that deuterated drugs are being scrutinized for altered effectiveness. "Depending on the drug class, this approach can potentially lead to a variety of beneficial effects, including longer duration of action, improved safety profile, reduced levels of toxic metabolites, and reduced inter-patient variability," said Pratik Shah, PhD, executive chairman of Auspex Pharmaceuticals Inc. (Vista, Calif.).

Auspex has filed more than 150 patent applications for deuterated drugs, and has received a patent on SD-254, an analogue of venlafaxine, the blockbuster selective serotonin-norepinephrine reuptake inhibitor (SNRI) drug for major depressive disorder, originally marketed by Wyeth as Effexor in 1993. Last October, Auspex announced initial Phase 1 clinical trial results of SD-254 in 16 healthy volunteers, reporting the deuterated drug was metabolized half as fast as venlafaxine and maintained effective levels in the body far longer, with potentially fewer side effects than the pioneer drug.

Last August, Concert Pharmaceuticals Inc. (Lexington, Mass.), another clinical stage biotech company, presented pre-clinical results for C-20081, a deuterium-containing oxazolidinone antibiotic, for possible once-daily oral and intravenous dosing. In the pre-clinical study, C-20081 had a 43% increase in plasma half-life compared to linezolid, which might allow for lower overall drug exposure, and improved tolerability for such serious bacterial infections as methicillin-resistant staphylococcus aureus (MRSA) and drug-resistant tuberculosis, the company said.

Concert has a Phase 1 clinical trial underway for CTP-347, a deuterated version of the antidepressant paroxetine, the selective serotonin reuptake inhibitor (SSRI) blockbuster drug sold as Seroxat and Paxil by GlaxoSmithKline beginning in 1992. Concert reported results in March for the drug, which it was testing to treat menopausal hot flashes. In a trial of 94 women, the deuterated version showed less metabolic inhibition than did regular paroxetine.

Like Auspex, Concert has filed more than 100 patent applications for a broad range deuterated drugs, with several notices of allowances received. The company received its first two patents in May. But the company has decided to shift attention this year from developing paroxetine to CTP-518, a deuterated protease inhibitor for treatment of HIV. "We believe this product has the potential to be the first HIV protease inhibitor that eliminates the need to co-administer with a protease inhibitor boosting agent, such as ritonavir," said Justine Koenigsberg, Concert’s senior director for corporate communications.

Because deuterated drugs have the same physicochemical properties as their originals, company officials are hopeful the FDA will streamline requirements for toxicological data and clinical trials, allowing manufacturers to bring the drugs to market more quickly and cheaply.

The pursuit of isomeric drugs is not new. Sepracor Inc. (Marlborough, Mass.) got its start in the early 1980s by tweaking single isomers and active metabolites from existing drugs and developing the chiral drugs as new entities having reduced side effects, greater potency, and new indications. The strategy paid off. Sepracor out-licensed rights to several compounds to Big Pharma, including Allegra (fexofenadine HCL, Sanofi Aventis), Clarinex (desloratadine, Schering-Plough), and XYZAL/XUSAL (levocetirizine, Sanofi Aventis).

Drug companies have since included chiral isomers on their patents. If deuterated drugs also take off, expect to see innovator companies including "heavy" versions in their patent applications as well. All this, of course, begs the question of whether the PTO will consider isomeric forms of a molecule to be an “obvious” application, and, thus, ineligible for patent protection.

"Essentially this issue will be one of breadth versus obviousness," said Ronald I. Eisenstein, a biotech patent attorney with the Nixon Peabody law firm in Boston. "If replacing the hydrogen with deuterium and improving the product can be shown to be a hit or miss proposition, a patent applicant will have a reasonable argument that a claimed product showing improved properties is not obvious," he said. "On the other hand, such an argument will make it easier for the PTO to reject generic claims to classes of compounds or even to particular compounds absent results."

Protia LLC, a small, privately-held Reno, Nevada-based biotech, appears to be taking this shotgun approach to patents. Over the past few months, the company has quietly filed hundreds of patent applications for deuterated versions of popular drugs, ranging from "deuterium-enriched" fingolimod (for multiple sclerosis) to atorvastatin (cholesterol reduction).

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