Prof Chris McGuigan Welsh School of Pharmacy Cardiff University An introduction to ProTides.

Small molecule drug discovery, particularly for viruses and cancer

HSV Cancer u

McGuigan Group Mission

CMV Smallpox

OA

VZV

HIV/AIDS

Hepatitis B/C

Antiviral Drugs?
DNA This works ts well into the WAG Priority of Health and biosciences
Avian u H5N1

Some Antiviral Nucleosides

O HN H2N HO N
acyclovir Zovirax herpes GSK

O
O
ganciclovir Cymevene CMV Roche

H C C

Br

N N

HN H2N N

N N

HN O HO N
BVDU Brivudin VZV Menarini

O HO Of 37 approved antivirals in UK, O O 18 (48%) are nucleoside-related.

NH
OH

OH

O
d4T Stavudine HIV BMS

HN O HO

Me 2009 BNF, 58, N

H2N HO N

NH2
N N
abacavir Ziagen HIV GSK 3TC lamivudine HepB O GSK

N N O

N O

HO

Nucleoside Drugs
O

NH

Thymidine
HO O

OH

Nucleoside Drugs
O

NH

AZT
HO O

N3

Nucleoside Drugs
O

NH

HO O

NH2

OH

deoxyguanosine

Nucleoside Drugs
O

NH

HO O

NH2

acyclovir

Nucs: Mechanism of Action

All nucleoside drugs require metabolic activation in their target cell to the bio-active phosphate forms:
O HN O HO N Me
O HO P O OH HN O O N O Me

Kinase Kinase
O OH O

a ct ive d4TTP
O P OH O O

O HN N O Me

Kinase

in

eO v i t ac
d4T

This is often the slow step.

HO P O P O OH

d4TMP

In general - this requirement is a disadvantage. Most often it limits clinical response.

The pre-formed phosphate (nucleotide) is of limited use as its charge prevents cell entry.

Lets try masking the charges?

X
A blocked nucleotide or ProTide

ProTides

GB Patent appl. 9505025, Mar 13 1995 McGuigan, J Med Chem, 1996, 39, 1748 .

Hepatitis C virus. HCV

170M infections worldwide: 3% of the Worlds population. 3-4M in USA. Many from transfusions. Current therapy poor. PEG-INF Ribavirin
O N N HO O OH OH N NH2

Cardiff-Inhibitex HCV candidate Inx189

Working with Inhibitex GA we have developed INX189, a ProTide of 2-CMeG, with nanomolar potency, and now in clinical trials for HCV.

HCV replicon with 14d treatment with Inx189

gemcitabine

NH2 N N O

MP (also TG)

S N N H N NH

FU

also capecitabine

O NH N H O
NH2 N N N F

HO O OH

NH2 N N N N Cl

cladribine
HO

cytarabine

NH2 N N O

udarabine

About 1 in 5 drugs O OH O are nucleosides (or their bases)

HO

HO OH approved anti-cancer O
OH

OH
NH2

OH
OMe N N N NH2

clofarabine
HO O

N N N F

nelarabine
Cl

N HO O OH OH

OH

Some Anticancer Nucleosides

Working with Nucana BioMed we are applying ProTides to cancer nucleosides, such as Gemcitabine.
NH2 N N HO O OH F
Hugh S Griffith CEO

Chris B Wood Chairman

Further information: mcguigan@cardiff.ac.uk