WELCOME

APPLICATION OF DEUTERIUM IN DRUG DISCOVERY

Presented by

RAHUL B S

M. Pharm Part II

Pharmaceutical Chemistry

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.

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.

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

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

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.

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)

DEUTERATION

It is the introduction of deuterium in a

chemical compound.

D2O

Deuterium gas

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.

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.

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

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.

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

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.

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

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.

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.

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.

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

FLUDALANINE.

The antibiotic fludalanine is broad and have potent

antibacterial activity, developed by Merck, the most

extensively studied deuterated drug candidate.

D6-NIFEDIPINE

One of the goal of deuteration was to increase the

half-life, improves patient compliance and hence both

efficacy and safety indirectly.

2-deutero-3-fluoro-D-alanine)

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.

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.

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.

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.

Pentoxifylline Lisofylline

CTP-499

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)

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.

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”.

DEUTERATED BENZOPYRAN

Deuterated benzopyran analogues as new COX-2 inhibitors.

The new molecules possess improved pharmacokinetic

profiles in rats compared to their nondeuterated analogues

DEUTERIUM IN DRUG DISCOVERY PROCESS

DISCOVERY PROCESS

The process by which a new drug is brought to

market.

Time consuming

Expensive

Understanding the disease

Target identification

Target validation

Lead identification

Lead optimization

Drug development

Pre clinical and clinical

studies.

Post marketing

surveillance

Lead optimization

Deuterium incorporation

DCE Platform - More Efficient and Less Expensive

Deuterated Chemical Entity Platform is the trade mark of Concert Pharmaceuticals.

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.

PATENTABILITY

The patentability of this approach is well

established, more than 100 USPTO-granted

patents directly covering deuterium substituted

versions of approved drugs.

Deuterium in drug discovery and clinical

development give way to tritium in drug discovery.

Deuterium in bioengineering.

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.

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.

REFERENCES1. 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

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