Selective incorporation of deuterium in place ofhydrogen (deuteration) - PDF document

Selective incorporation of deuterium in place ofhydrogen (deuteration) has the unique effect ofretaining the biochemical potency and selectivity ofphysiologically active compounds while, in selectalter their overall therapeutic profile. In favourablecases, this modification has the potential to have apositive impact effect on safety, efficacy and/ortolerability. By starting from compounds with well-approved drugs Ð deuteration potentially provides a unique, streamlined approach to creatingsignificantly differentiated, patentable new medicinesthat can address important unmet medical needs.Deuterated compounds have been widely studied inmetabolic or pharmacokinetic probes. Although nodeuterated compound has been approved as a humanmedicine, there do not appear to be any economic orregulatory reasons preventing the registration ofdeuterium-containing drugs. The early clinicalevaluation of several candidate compounds has beenencouraging, supporting the potential for importantnew deuterated drugs to reach the market.WHAT IS DEUTERIUM? By Roger Tung atConcert PharmaceuticalsThe Development of Deuterium-Containing DrugsInnovations in Pharmaceutical Technology undetectable to quite substantial. The observedmagnitude and even direction of the KIEs areunpredictable, and depend on a compoundÕs substituentsRIUM SAFETY AND PHARMACOLOGYThe effects of deuterium have been widely explored compounds became available. In general, deuterium hasremarkably low systemic toxicity. Single-celled organismscan often be grown in conditions of full deuteration.Lower organisms including fish and tadpoles reportedlysurvive in at least 30 per cent DO. Mice and dogs do notdisplay visible effects from long-term replacement of atleast 10-15 per cent of body fluid hydrogen withdeuterium, although concentrations above 25 per centare broadly toxic to those species. Humans can tolerate high levels of deuterium in bodyfluids. Acute exposure levels of 15-23 per cent deuteriumreplacement in whole body plasma have been reportedwith no evident adverse effects (5). Deuterated water is renally excreted by humans with a half-life of about As a result of the KIE, deuteration can result in altered metabolism patterns. We are not aware of cases of deuteration resulting in the formation ofunique metabolites in animals that were not producedby the all-hydrogen analogue. However, reduced ratesof metabolism and metabolic shunting, where theratio of metabolites is changed, have been reported(6,7). Although rarely reported in the literature, wehave also observed several cases where selectivedeuteration increases the rate of metabolic clearancein vitroWe have found it convenient to conceptualise thepharmacological effects of deuteration in three majorcategories, as illustrated in Figure 1. Panel 1 illustratescases where the major effect of deuteration is to reducethe rate of systemic clearance. As a result, thebiological half-life of the compound is increased.Potential drug benefits could include a reduction inexposure with decreased peak levels and increasedtrough levels. This could result in a lower incidence ofside effects and enhanced efficacy, depending on theparticular drugÕs pharmacokinetic/pharmacodynamicrelationship.The second panel illustrates a predominantly pre-systemic effect of deuteration, which we haveobserved in a number of instances. In these cases,reduced rates of (usually oxidative) metabolism in thegut wall and/or liver result in a larger percentage ofunmetabolised drug reaching systemic circulation. InDeuterated drugs showing this effect may have reduceddosing requirements and produce lower metaboliteloads. Since gastrointestinal irritation has been related toconcentration for certain drugs, this effect could allowenhanced tolerability and/or the ability to achieve aThe third panel illustrates metabolic shunting. Manydrugs are metabolised in complex patterns, sometimesforming both active and innocuous metabolites. We andothers have demonstrated that the deuterium KIE canresult in reduced formation of toxic or reactivemetabolites, as well as increased formation of desirableactive metabolites (7). Clear potential benefits in termsof human medicines are apparent. A: Reduced systemic clearance resulting in increased half-life. B: Decreased pre-systemic metabolism resulting in higherbioavailability of unmetabolised drug. C: Metabolic shunting resulting in reduced exposure to undesirable metabolites Panel APanel BPanel CM1M2TimeTimeDrug concentrationDeuterated drugToxic CLINICAL EVALUATIONDeuterated compounds have a long history of use inhumans as metabolic and pharmacokinetic probes. Incontrast, there have been few reports of deuteratedcompounds being studied as potential new drugs.Fludalanine (2-deutero-3-fluoro-D-alanine),developed by Merck, appears to be the mostextensively studied deuterated drug candidate.Fludalanine, combined with cycloserine, displaysbroad and potent antibacterial activity. Its all-hydrogen analogue is also a highly effective anti-infective agent, but preclinical studies reportedlyfluorolactate, a toxin that caused brain vacuolisation(8). Kahan reported in a recent letter that thedeuterium KIE reduced 3-fluorolactate production towhat were deemed acceptable levels in healthyvolunteers. However, higher 3-fluorolactate levelswere observed in patients, potentially resulting frommetabolic derangements. Studies on fludalanine werediscontinued at Phase IIb.Several other potential novel deuterated drugs haveentered clinical evaluation. Concert Pharmaceuticalsrecently presented Phase I results on CTP-347, aselectively deuterated analogue of paroxetine for thetreatment of hot flashes (9). Low dose paroxetinereportedly has good efficacy in treating hot flashes.However, in patients potentially benefiting from suchtherapy, such as post-menopausal women and cancerpatients receiving endocrine disrupting agents,paroxetine use can be complicated or contraindicated asit causes extensive drug-drug interactions (DDIs) withother drugs.The cause of these DDIs is believed to bepredominantly irreversible inactivation of the hepaticenzyme CYP2D6. This inactivation is believed to bedue to a highly reactive metabolite that covalently bindsthe active site of CYP2D6. In vitroCYP2D6 inactivation, apparently due to metabolicshunting preventing the formation of the reactivemetabolite (see Figure 2) (10). CTP-347 demonstratedequivalent serotonin reuptake inhibition and selectivityto paroxetine, and was indistinguishable fromparoxetine in a battery of over a hundred receptor andsingle- and multiple-ascending dose clinical trial. Themultiple-dose subjects initially received a single dose ofdextromethorphan, followed by 14 days of treatmentdextromethorphan. Dextromethorphan acts as aselective probe for CYP2D6 activity. Subjects receivingCTP-347 retained substantially greater ability tometabolise dextromethorphan than occurs withparoxetine, correlating well with in vitroFigure 3) (9). Minor CYP2D6 inhibition was observedat higher CTP-347 doses, consistent with reversible,competitive inhibition seen in vitro. The study is also Figure 2:Proposed pathway for inactivation of CYP2D6 by paroxetine metabolite.Structures in red show the putative reactive metabolite and resultant inactivated enzyme Phase Ib study. Y-axis shows the ratio of intact excreted dextromethorphan versus10mg QD10mg BID 20mg QD40mg QD20mg (20mg/day)Paroxetine* can be utilised to ameliorate drug-drug interactions Concert recently announced initiation of multipleascending dose studies with its development candidateCTP-518, an HIV protease inhibitor (PI) based on theatazanavir scaffold. Due to its favourable antiviralpotency and pharmacokinetic profile, CTP-518 isbeing developed to be optimally administered withoutthe need for ritonavir, a pharmacokinetic booster. Thecurrent standard of care is to co-administer allmarketed HIV PIs with ritonavir. However, ritonavirco-dosing complicates dosing regimens and isassociated with nausea and increased blood lipids,including LDL cholesterol and triglycerides.Eliminating the need for this agent would therefore beclinically advantageous.Auspex Pharmaceuticals is developing SD-254, aselectively deuterated analogue of the antidepressantvenlafaxine. In October 2008, Auspex issued a pressrelease on their SD-254 Phase I healthy volunteer studyin which the compound reportedly Òexhibited apharmacokinetic profile that appears to be superior tothat of venlafaxineÓ. Berolina innovative Research and Development ServicesPharma (BiRDS Pharma) is developing BDD-10103, adeuterated analog of the muscle relaxant tolperisone.Specific data have not been publicly released, but BiRDSreported Òenhanced overall bioavailability of BDD-10103 compared to tolperisoneÓ.CONCLUSIONDeuterium offers a subtle, but sometimes powerful,medicinal chemistry tool that has received littleattention to date in the context of new drugs. Selectivedeuteration retains biochemical potency and selectivity,overall pharmacological profile of the resultingcompounds. When applied to compounds with well-understood therapeutic utility, selective deuteration canbe a unique risk-reduced approach to creating newchemical entity drugs that address significant unmetmedical needs. Several companies are focused ondeuteration as a business model and have receivedsubstantial funding to pursue the approach. With moreevaluation, it appears increasingly likely that theapproach will succeed in producing important new1. Marter WL, Hayes DW and Jones DW, Deuteriumand Tritium, Part A. Deuterium, InJC and Cunningham WA, Eds, Marcel Dekker, 19822. Di Costanzo L, Moulin M, Haertlein M 3. Bell RP, Recent advances in the study of kinetic4. Fisher MB, Henne KR and Boer J, The complexities5. Blagojevic N, Storr G, Allen JB heavy water in boron neutron capture therapy, Dosimetry & Treatment Planning for Neutron Capture6. Kushner DJ, Baker A and Dunstall TG,7. Mutlib AE, Gerson RJ, Meunier PC Toxicol Appl Pharmacol8. Kahan F, A deuterated drug that almost succeeded,9. Uttamsingh V, Wells D, Soergel D Healthy Women, Presented at the 38th AmericanCollege of Clinical Pharmacology, 200910. Morales A, Gallegos R, Jones A a Deuterated Analog of Paroxetine With Greatly Roger Tungis the Scientific Founder, President and CEO ofConcert Pharmaceuticals, which was based on a series ofpatent applications he filed in 2005. He has over 20 years ofwith Merck, Vertex and Concert. Roger co-invented the HIV, both marketed byGlaxoSmithKline, was Co-Development Head of Agenerasethrough US and EMEA approvals, and oversaw the discovery of HCV and cysticfibrosis agents now in Phase III. He holds a BA in Chemistry from Reed College(Portland, OR) and a PhD from the University of Wisconsin (Madison, WI). Email: ir@concertpharma.com