Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Malmlöf, Torun; Rylander, Daniella; Alken, Rudolf-Giesbert; Schneider, Frank; Svensson, Torgny H.; Cenci, M. Angela; Schilström, Björn

doi:10.1016/j.expneurol.2010.07.018

Cited by 27 publications

(22 citation statements)

References 348 publications

(500 reference statements)

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“…Considering that the study was not powered to demonstrate bioequivalence, the systemic exposures to SD‐1077 and L‐DOPA were comparable, consistent with the findings that deuterium substitution did not affect the peripheral PK after intraperitoneal administration in rats 20. This finding is also reflected by similar amounts of unchanged drug excreted to urine following SD‐1077/CD and L‐DOPA/CD and consistent with the lack of the impacted deuterated positions in the decarboxylase reaction forming DA from the parent.…”

Section: Discussionsupporting

confidence: 74%

“…A deuterium effect on absorption is not to be expected because no difference in the binding of regular DA and deuterated DA to the DA transporter was found in vitro 18. The effect on deuterated DA turnover in the periphery is supportive by experiments in rats 20 where a lower equipotent dose was demonstrated. The magnitude of the effect in the human brain cannot be readily predicted from peripheral findings because MAO distribution, release, reuptake and storage influence DA turnover.…”

Section: Discussionmentioning

confidence: 92%

“…The concentrations time curves of striatal DA observed following intraperitoneal administration to healthy rats, d3‐(2S)‐2‐amino‐2,3,3‐trideuterio‐3‐(3,4‐dihydroxyphenyl) propanoic acid show a prolonged increase without significant higher peak levels as compared to L‐DOPA 19. The fact that an equipotent dose of d3‐(2S)‐2‐amino‐2,3,3‐trideuterio‐3‐(3,4‐dihydroxyphenyl) propanoic acid induced fewer and not more dyskinesias at the same dose than L‐DOPA in the 6‐OHDA rodent model of Parkinson's disease 20 supports the potential of the drug to reduce fluctuations. To confirm central effects of the drug in humans, the efficacy and safety of SD‐1077 needs to be investigated in patients.…”

Section: Discussionmentioning

confidence: 95%

“…Observation of a decreased DOPAC/DA ratio confirmed that slower breakdown by MAO contributed to lower DA turnover. In rodent models of Parkinson's disease d3‐(2S)‐2‐amino‐2,3,3‐trideuterio‐3‐(3,4‐dihydroxyphenyl) propanoic acid was more potent at reducing motor behavior deficits than L‐DOPA 18, 19, 20. Approximately 60% of the traditional L‐DOPA dose was equipotent as defined by the dose that produced 50% of the maximally observed motor performance and induced less dyskinesia in chronic treatment 20.…”

Section: Introductionmentioning

confidence: 99%

“…In rodent models of Parkinson's disease d3‐(2S)‐2‐amino‐2,3,3‐trideuterio‐3‐(3,4‐dihydroxyphenyl) propanoic acid was more potent at reducing motor behavior deficits than L‐DOPA 18, 19, 20. Approximately 60% of the traditional L‐DOPA dose was equipotent as defined by the dose that produced 50% of the maximally observed motor performance and induced less dyskinesia in chronic treatment 20. In 6‐OHDA‐lesioned rats the observed motor performance showed similar magnitude to that of L‐DOPA in combination with the http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2490 inhibitor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6639, an effect attributed to decreased metabolism of L‐DOPA by MAO‐B 18.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects

Schneider

Erisson

Beygi

et al. 2018

Brit J Clinical Pharma

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AimsSD‐1077, a selectively deuterated precursor of dopamine (DA) structurally related to L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD‐1077.MethodsPlasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD‐1077 dose were compared to 150 mg L‐DOPA, each in combination with 37.5 mg carbidopa (CD) in a double‐blind, two‐period, crossover study in healthy volunteers (n = 16).ResultsGeometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD‐1077 vs. L‐DOPA for Cmax, AUC0–t, and AUC0–inf were 88.4 (75.9–103.1), 89.5 (84.1–95.3), and 89.6 (84.2–95.4), respectively. Systemic exposure to DA was significantly higher after SD‐1077/CD compared to that after L‐DOPA/CD, with GMRs (90% CI) of 1.8 (1.45–2.24; P = 0.0005) and 2.06 (1.68–2.52; P < 0.0001) for Cmax and AUC0–t and a concomitant reduction in the ratio of 3,4‐dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O‐methyltransferase (COMT) reaction, 3‐methoxytyramine (3‐MT) and 3‐O‐methyldopa (3‐OMD) with GMRs (90% CI) for SD‐1077/CD to L‐DOPA/CD for 3‐MT exposure of 1.33 (1.14–1.56; P = 0.0077) and 1.66 (1.42–1.93; P < 0.0001) for Cmax and AUC0–t, respectively and GMRs (90% CI) for 3‐OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0–t. SD‐1077/CD exhibited comparable tolerability and safety to L‐DOPA/CD.ConclusionsSD‐1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L‐DOPA/CD combination. A single dose of SD‐1077 is safe for further clinical development in Parkinson's disease patients.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects

Schneider

Erisson

Beygi

et al. 2018

Brit J Clinical Pharma

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Rhodium‐Catalyzed Stereoselective Deuteration of Benzylic C–H Bonds via Reversible η⁶‐Coordination

Kang

Chen

et al. 2022

Angewandte Chemie

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We report a convenient method for benzylic H/D exchange of a wide variety of substrates bearing primary, secondary, or tertiary C−H bonds via a reversible η6‐coordination strategy. A doubly cationic [CpCF3RhIII]2+ catalyst that serves as an arenophile facilitates deprotonation of inert benzylic hydrogen atoms (pKa>40 in DMSO) without affecting other hydrogen atoms, such as those on aromatic rings or in α‐positions of carboxylate groups. Notably, the H/D exchange reactions feature high stereoretention. We demonstrated the potential utility of this method by using it for deuterium labeling of ten pharmaceuticals and their analogues.

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Cobalt‐Catalyzed Asymmetric Deuteration of α‐Amidoacrylates for Stereoselective Synthesis of α,β‐Dideuterated α‐Amino Acids

Song

Ren

et al. 2023

Angewandte Chemie

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Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Cited by 27 publications

References 348 publications

Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects

Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects

Rhodium‐Catalyzed Stereoselective Deuteration of Benzylic C–H Bonds via Reversible η⁶‐Coordination

Cobalt‐Catalyzed Asymmetric Deuteration of α‐Amidoacrylates for Stereoselective Synthesis of α,β‐Dideuterated α‐Amino Acids

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Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias

Cited by 27 publications

References 348 publications

Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects

Pharmacokinetics, metabolism and safety of deuterated L‐DOPA (SD‐1077)/carbidopa compared to L‐DOPA/carbidopa following single oral dose administration in healthy subjects

Rhodium‐Catalyzed Stereoselective Deuteration of Benzylic C–H Bonds via Reversible η6‐Coordination

Cobalt‐Catalyzed Asymmetric Deuteration of α‐Amidoacrylates for Stereoselective Synthesis of α,β‐Dideuterated α‐Amino Acids

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Rhodium‐Catalyzed Stereoselective Deuteration of Benzylic C–H Bonds via Reversible η⁶‐Coordination