Deuterium substitution improves therapeutic and metabolic profiles of medicines

Deuterium substitution yields potential therapeutic benefits including improved safety, efficacy, tolerability and convenience

2015-07-01

(Press-News.org) Lexington, Mass., July 1, 2015 - Substituting deuterium for certain hydrogen atoms in molecules has been shown to enhance the metabolic properties of a number of drugs and provides a promising approach to the discovery and development of innovative drug products. The deuterium chemistry approach has the potential to reduce the high failure rates of conventional drug development by building on the known pharmacology of existing compounds and leveraging their desirable therapeutic properties. Selective deuterium substitution as a means of ameliorating unwanted clinically relevant pharmacokinetic drug interactions caused by the widely-used antidepressant agent paroxetine (marketed as Paxil®) was demonstrated by researchers at Concert Pharmaceuticals and published in the July 2015, print edition of J. Pharmacol. Exp. Ther. Deuterated compounds will generally be expected to retain the biochemical potency and selectivity of their corresponding hydrogen analogs. In select cases deuterium may impart a different metabolic profile, and the altered metabolic properties of these deuterated compounds may lead to therapeutic benefits such as improved safety, efficacy, tolerability, convenience, and reduced drug-drug interactions, as is shown in the publication. The effects, if any, of deuterium substitution on metabolic properties are highly dependent on the specific carbon positions where deuterium is substituted. Furthermore, the metabolic effects of deuterium substitution, if any, are unpredictable a priori, even in compounds that have similar chemical structures. "This research highlights the great potential for rapidly creating best-in-class medicines with more desirable metabolic properties while reducing drug development using our Deuterated Chemical Entity Platform," stated James Cassella, Ph.D., Chief Development Officer of Concert Pharmaceuticals. "Concert has clearly shown that selective deuterium substitution can meaningfully improve the metabolic fate of drugs across a variety of important parameters." In the published research, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium using Concert's precision deuteration platform. The new chemical entity, CTP-347, demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, compared to paroxetine. Metabolism of paroxetine creates a reactive metabolite that irreversibly inactivates the important metabolic enzyme cytochrome P450 2D6 (CYP2D6). As a result, paroxetine therapy can alter the metabolism of many other drugs that are CYP2D6 substrates, resulting in significant and undesirable alterations of their blood levels. CTP-347 produces reduced levels of the reactive metabolite, thereby helping to preserve CYP2D6 function. CTP-347 was demonstrated to significantly reduce drug-drug interactions, relative to paroxetine, when tested with two other drugs that are metabolized by CYP2D6: tamoxifen (in vitro) and dextromethorphan (in humans). CTP-347 and paroxetine are both metabolized by CYP2D6, so CTP-347 was also clinically metabolized more rapidly and exhibited a lower pharmacokinetic accumulation index than paroxetine. CTP-347 is believed to be the first clinical compound where precision deuteration was applied to reduce drug-drug interactions without affecting its intrinsic pharmacology.

INFORMATION:

About Concert Pharmaceuticals Concert Pharmaceuticals is a clinical stage biopharmaceutical company focused on applying its DCE Platform® (deuterated chemical entity platform) to create novel small molecule drugs. This approach starts with approved drugs, advanced clinical candidates or previously studied compounds that have the potential to be improved with deuterium substitution to enhance clinical safety, tolerability and efficacy. The Company is developing a broad pipeline targeting CNS disorders, genetic diseases, renal disease, inflammatory diseases and cancer. For more information, please visit http://www.concertpharma.com.

Concert Pharmaceuticals Inc., the CoNCERT Pharmaceuticals Inc. logo and DCE Platform are registered trademarks of Concert Pharmaceuticals, Inc.

ELSE PRESS RELEASES FROM THIS DATE:

Experimental drug combined with standard chemo may shrink ovarian cancers

2015-07-01

Working in cell cultures and mice, researchers at Johns Hopkins have found that an experimental drug called fostamatinib combined with the chemotherapy drug paclitaxel may overcome ovarian cancer cells' resistance to paclitaxel. Scientists elsewhere are already testing fostamatinib in people with lymphoma and idiopathic thrombocytopenia purpura, an autoimmune disorder. Based on results of the current study described in a report online June 18 in the journal Cancer Cell, Johns Hopkins researchers say they are planning a phase I clinical trial to test the paclitaxel-fostamatinib ...

Producing spin-entangled electrons

2015-07-01

A team from the RIKEN Center for Emergent Matter Science, along with collaborators from several Japanese institutions, have successfully produced pairs of spin-entangled electrons and demonstrated, for the first time, that these electrons remain entangled even when they are separated from one another on a chip. This research could contribute to the creation of futuristic quantum networks operating using quantum teleportation, which could allow information contained in quantum bits--qubits--to be shared between many elements on chip, a key requirement to scale up the power ...

Warts and all: How St. John's Wort can make you sick

2015-07-01

St John's Wort can produce the same adverse reactions as antidepressants, and serious side effects can occur when the two are taken together, according to new University of Adelaide research. In a study published this month in the journal, Clinical and Experimental Pharmacology and Physiology, researchers compared the pattern of spontaneous reported adverse drug reactions to St John's Wort, a herbal treatment for depression, and fluoxetine, a commonly prescribed antidepressant. They found the adverse reactions were the same for people who took St John's Wort as it was ...

Europe, Siberia and in between: Caucasian populations of non-biting midges

2015-07-01

A research in the North Caucasus, conducted by a group of Russian scientists over three years, has revealed an intermediate distribution of Caucasian populations of non-biting midges between Europe and Siberia. Their observations also proved some interesting morphological distinctions between the studied populations and the previously researched ones from Europe and Siberia. Their results have been published in the open-access journal Comparative Cytogenetics. The study on karyotypical and morphological peculiarities of Ch. bernensis is a part of the investigation of ...

Improving insulation materials, down to wetting crossed fibers

2015-07-01

Sandcastles are a prime example of how adding a small amount of liquid to a granular material changes its characteristics. But understanding the effect of a liquid wetting randomly oriented fibres in a fibrous medium remains a mystery. Relevant to the building industry, which uses glass wool, for instance, this phenomenon can be better understood by studying the behaviour of a liquid trapped between two parallel fibres. It can either remain in the shape of a drop or spread between the fibres into a long and thin column of liquid. Now, scientists have demonstrated that the ...

The bizarre mating habits of flatworms

2015-07-01

Failing to find a mating partner is a dent to the reproductive prospects of any animal, but in the flatworm species Macrostomum hystrix it might involve a real headache. Zoologists from the Universities of Basel and Bielefeld have discovered the extraordinary lengths to which this animal is willing to go in order to reproduce - including apparently injecting sperm directly into their own heads. The academic journal Proceedings of the Royal Society B has published their findings. The absence of a mate usually spells disaster for sexually reproducing animals. However, some ...

Clues to inner atomic life from subtle light-emission shifts

2015-07-01

Atoms absorb and emit light of various wavelengths. Physicists have long known that there are some tiny changes, or shifts, in the light that gets absorbed or emitted, due to the properties of the atomic nucleus. Now, a team of scientists has elucidated the so-called hyperfine structure of cadmium atoms. Relying on a method called laser spectroscopy, they have measured variations in the energy transition within cadmium atom - Cd in the periodic table. They studied a chain of isotopes with an odd number of neutrons ranging from 59 in 107Cd to 75 in 123Cd. From these high-precision ...

Sleep deprivation could reduce intrusive memories of traumatic scenes

2015-07-01

A good night's sleep has long been recommended to those who have experienced a traumatic event. But an Oxford University-led study provides preliminary experimental work suggesting it could actually be the wrong thing to do. The research, conducted in Oxford's Wellcome Trust-funded Sleep and Circadian Neuroscience Institute (SCNi) and published in the journal Sleep, showed that sleep deprivation might prevent people from consolidating memories of experimental trauma (emotional film clips in the study), reducing their tendency to experience flashbacks. Dr Kate Porcheret, ...

Level I trauma experience prepares surgeons for battle

2015-07-01

(SACRAMENTO, Calif.) -- Soldiers injured during the conflicts in Iraq and Afghanistan have the highest survival rates in history, thanks to the availability of surgeons skilled in combat care. But combat-ready surgical skills are hard to sustain off the battlefield. "A lot of knowledge builds up in the military medical enterprise during times of war," said Joseph Galante, who chairs the UC Davis Division of Trauma, Emergency and Critical Care Surgery and is a commander in the U.S. Navy Reserves. "When peacetime comes, that knowledge can slide. We need to identify ways ...

Seafood supply altered by climate change

2015-07-01

The global supply of seafood is set to change substantially and many people will not be able to enjoy the same quantity and dishes in the future due to climate change and ocean acidification, according to UBC scientists. These findings were released today in Japan by the Nereus program, an international research team led by UBC scientists and supported by the Nippon Foundation. The Nereus program was formed to study the future of the world's oceans and seafood resources. Today it released a summary of the first phase of its research in a report titled 'Predicting Future ...