APPLICATION OF DEUTERIUM IN DRUG DISCOVERY

2. APPLICATION OF DEUTERIUM
IN DRUG DISCOVERY
Presented by
RAHUL B S
M. Pharm Part II
Pharmaceutical Chemistry

3. DEUTERIUM
Deuterium is a naturally-occurring, stable,
nonradioactive isotope of hydrogen.
Contains one neutron and one proton.
It was discovered by Harold Urey in 1931.

5. Occurrence in nature - 1 part in 6420 hydrogen.
Concentration ranges from 0.0156% in sea water
to 0.0139% in fresh water.
Heavy water - the simplest deuterium-containing
compound, differs from ordinary water.

6. Production is mainly by Girdler sulfide (GS)
process, electrolysis of water.
India has seven heavy water production plant.
Is used as coolant and moderator in nuclear
reactors

7. DEUTERIUM KINETIC ISOTOPE EFFECT
(DKIE)
The relative change in the rate of a chemical
reaction upon substitution of an atom in the
reactants by one of its isotopes.
The ratio of rate constants for the reactions
involving the light (kH) and the heavy (kD)
isotopically substituted reactants.
DKIE = kH/kD

8. KIE is used to determine reaction
mechanisms.
D-C bonds are about 6 to 10 times more
stable than the corresponding C-H.
Cleavage of the C-D bond requires greater
energy than the C-H bond.

9. C-D bonds have a lower vibrational
frequency and therefore lower zero-point energy
than a corresponding C-H bond.
lower zero-point energy results higher
activation energy and a slower rate for C-D bond
cleavage.
Primary Deuterium Isotope Effect (DIE)

11. DEUTERATION
It is the introduction of deuterium in a
chemical compound.
 D2O
 Deuterium gas

12. DEUTERIUM SAFETY AND PHARMACOLOGY
The body of the average human adult contains
about 2 g of deuterium.
Single-celled organisms can survive on full
deuterated environment.
Lower organisms like fish and tadpoles will
survive in 30% D2O.

13. Mice and dogs do not display visible effects
from long-term replacement of 10-15% of body fluid
hydrogen with deuterium.
Concentrations above 25% are broadly toxic
to those species.
Humans can also tolerate high exposure to
deuterium in body fluids.

14. No toxicity was observed on acute exposure
of 15-23% deuterium replacement in whole body
plasma.
D2O is excreted by humans via the urine with
a Half -life of about 10 days similar to that of H2O.
MSDS

15. DEUTERIUM IN DRUG DISCOVERY
Bio isosterism
Replacement of functional groups having
similar properties is known as Bioisosteric
replacement .
Bioisosteres are groups or molecules which
have chemical and physical properties producing
broadly similar biological properties.

16. Molecules are commonly assigned on the
basis of the number of valence electrons of an
atom or a group of atoms rather than on the total
number of orbital electrons.
BIOISOSTERES OF HYDROGEN
Monovalent bioisosteres
F, Cl, I, Br
OH, NH2,CH3,SH, CF3

17. DIFFERENCES BETWEEN A C−H BOND
AND A C−D BOND
 C−D bond is a bit shorter,
 Reduced electronic polarizability
 Lesser Hyperconjugative stabilization of adjacent bonds
Weaker van der Waals stabilization
 Intramolecular volume and transition state volume are
difficult to predict.

18. DEUTERIUM THE BEST BIOISOSTERES
OF HYDROGEN
Common C−H replacement is C−F in drug
discovery.
Produce differences in so many properties
relative to the hydrogen.
Fluorine has a van der Waals volume almost
100% larger than hydrogen, Electronegative,
Hydrogen bond acceptor.
Fluorinated drug is different in every manner

19. Several parameters may change by a C-F
replacement.
• Mechanism of action
• Target binding affinity
• PK/PD relationship
• Permeability
• Solubility in all vehicles
• Protein binding/serum binding
• GI tolerability
• CNS tolerability
• BBB penetration
• Volume of distribution etc.

20. C-D will not generally exhibit a clinically
measurable change in properties.
C-D replaced products are indistinguishable
from its protium analogue,
• Invitro pharmacodynamics (PD)
• Physicochemical properties,
• Biological properties
The C−D bonds, more stable to oxidative
processes because of the kinetic isotope effect.

21. EMPLOYING DEUTERIUM IN THE DESIGN
AND STUDY OF NEW MEDICINES
Deuteration will enhance drug’s pharmacokinetic,
pharmacodynamic, or toxicological properties.
Examples of clinically tested deuterated drugs
D1-HALOTHANE
Halothane is a volatile anaesthetic, is known to
cause hepatotoxicity.
Acyl chloride is the reactive intermediate
responsible for forming DNA adducts and likely
other adducts, in the liver.

22. D1-halothane was developed, and a dramatic reduction
in DNA adducts.

23. FLUDALANINE.
The antibiotic fludalanine is broad and have potent
antibacterial activity, developed by Merck, the most
extensively studied deuterated drug candidate.
D6-NIFEDIPINE
2-deutero-3-fluoro-D-alanine)
One of the goal of deuteration was to increase the
half-life, improves patient compliance and hence both
efficacy and safety indirectly.

24. Longer half-life should lead to decreased “withdrawal
effects” in many agents, again a safety improvement.
D6-NIFEDIPINE, deuterated nifedipine gave rise to
a 34% increase in efficacy in rodents.

25. NEVIRAPINE
Nevirapine is a non-nucleoside reverse
transcriptase inhibitor for the treatment of HIV
infection.
ADR- high incidence of skin rash and hepatotoxicity.
The hepatotoxicity and skin rash is due to the
CYP metabolism produces a radical intermediate.

26. Deuterated Nevirapine reduces covalent binding to
hepatic proteins, and produce less hydroxy metabolite which
reduced the incidence and severity of the rashes in both
mouse and rat models.

27. CLINICAL TRIALS OF DEUTERATED
DRUGS
CTP-499 for Diabetic Nephropathy
CTP- 499 is a drug candidate of Concert pharmaceuticals
for diabetic nephropathy in type 2 diabetics.
CTP-499 is an analogue of Lisofylline an active metabolite of
Pentoxifylline
CTP-499 is created by replacing several key hydrogen atoms
with deuterium.

28. Pentoxifylline Lisofylline
CTP-499

29. CTP-347: Deuterium Modification of Paroxetine
CTP-347, a selectively deuterated analogue of paroxetine.
CTP-347 was designed to eliminate the irreversible
inhibition of the metabolizing enzyme (CYP2D6)

30. AVP-786 :deuterated dextromethorphan
AVP-786 is a combination of a deuterated
dextromethorphan and ultra-low dose quinidine, developed
by Avanir Pharmaceuticals in major depressive disorders.

31. SD-254
SD-254 is deuterated analogue of the
antidepressant venlafaxine developed by Auspex
Pharmaceuticals.
SD-254 Phase I exhibited a pharmacokinetic
profile superior to venlafaxine”.

32. DEUTERATED BENZOPYRAN
Deuterated benzopyran analogues as new COX-2
inhibitors.
The new molecules possess improved pharmacokinetic
profiles in rats compared to their nondeuterated analogues

33. DEUTERIUM IN DRUG DISCOVERY
PROCESS
DISCOVERY PROCESS
The process by which a new drug is brought to
market.
Time consuming
Expensive

34. Understanding
the disease
Target
identification
Target
validation
Lead
identification
Lead
optimization
Drug
development
Pre clinical and
clinical studies.
Post
marketing
surveillance

35. Deuterium
incorporation
Lead
optimization

36. DCE Platform - More Efficient and Less
Expensive
Deuterated Chemical Entity Platform is the trade
mark of Concert Pharmaceuticals.

37. Traditional methods of drug discovery which
involve lengthy processes with high failure rates.
Begins with approved drugs, advanced clinical
compounds or previously studied compounds.
Enable drug discovery and clinical
development more efficient and less expensive than
conventional drug research and development.

38. Deuterium in drug discovery and clinical
development give way to tritium in drug discovery.
Deuterium in bioengineering.
PATENTABILITY
The patentability of this approach is well
established, more than 100 USPTO-granted
patents directly covering deuterium substituted
versions of approved drugs.

39. CHALLENGES IN
DEUTERIUM INCORPORATION
Deuterium/Hydrogen exchange within the
physiological Environment.
Deuterium retards metabolism at one site.
(“metabolic switching” or “metabolic shunting”)
Suppression of one metabolic pathway
promotes metabolism at another site.

40. CONCLUSION
 Deuterium incorporation.
 Patentable new medicines.
 Retains biochemical potency and selectivity,
enable PK/PD.
 Risk-reduced approach to creating new chemical
entity drugs.
 New medicines.

41. REFERENCES
1. Thomas G. Gant, Using Deuterium in Drug Discovery: Leaving the Label in
the Drug, J. Med. Chem., 2014, 57 (9), pp. 3595–3611.
2. Deuterium Modification as a New Branch of Medicinal Chemistry to Develop
Novel, Highly Differentiated Drugs Articles drug development and delivery.
3. Deuterium Medicinal chemistry: A New approach of drug discovery and
development. MEDCHEM NEWS No.2 MAY 2014.
4. The Development of Deuterium-Containing Drugs, By Roger Tung at Concert
Pharmaceuticals.
5. Studies with Deuterated Drugs, MARTIN I. BLAKE , HENRY L. CRESPI , and
JOSEPH J. KATZ, Journal of Pharmaceutical Sciences, Val. 64, No. 3, March
1975 I367.
6. Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2
Inhibitors with Improved Pharmacokinetic Properties, Yanmei Zhang et al.
ACS Medicinal Chemistry Letters 2014/08/14

42. 7. The kinetic deuterium isotope effect as applied to metabolic deactivation of
imatinib to the des-methyl metabolite, CGP74588. Paul W. Manley ⇑, Francesca
Blasco, Jürgen Mestan, Reiner Aichholz. Bioorg. Med. Chem. 21 (2013) 3231–3239.
8. Deuterium Isotope Effects on Drug Pharmacokinetics. I. System- Dependent
Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs, Raman
Sharma, Timothy J. Strelevitz, Hongying Gao, DRUG METABOLISM AND
DISPOSITION Vol. 40, No. 3 625–634, 2012.
9. Deuterium Modification as a New Branch of Medicinal Chemistry to Develop
Novel, Highly Differentiated Drugs July/August 2012, Posted Date: 7/14/2012