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For more presentations and information visit http://www.pharmaxchange.info. DIRECT FACTOR Xa INHIBITOR AS ANTICOAGULANT. PREET PAL SINGH SIDHU DEPT OF MEDICINAL CHEMISTRY SCHOOL OF PHARMACY, VCU. OVERVIEW. For more presentations and information visit http://www.pharmaxchange.info.

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DIRECT FACTOR Xa INHIBITOR

AS ANTICOAGULANT

PREET PAL SINGH SIDHU

DEPT OF MEDICINAL CHEMISTRY

SCHOOL OF PHARMACY, VCU.


OVERVIEW

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  • Introduction

  • Comparison with current therapy.

  • Natural inhibitors of Factor Xa.

  • Structural details of active site.

  • Trend in Factor Xa inhibitors.

  • Rivaroxaban

  • - SAR

  • - Synthesis

  • - Crystal structure

  • - pharmacokinetic profile

  • 7. Apixaban

  • - Synthesis

  • - Crystal structure

  • - Pharmacokinetic profile

  • 8. Conclusion.


INTRODUCTION

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  • Factor Xa is K-dependent serine protease.

  • Molecular Wt is 45 K.

  • Factor Xa occupies the pivotial position in coagulation cascade.

  • Factor X is zymogen of Factor Xa.

  • Circulates in plasma as a light- and heavy-chain held together by a disulfide bond.

  • N-terminal light chain contain GLA and two epidermal growth factor-like domain.

  • C-terminal heavy chain contain the trypsin-like catalytic domain.

  • First Factor Xa deficiency was described in 1950s.


INTRODUCTION

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Two physiological inhibitor:

1)Tissue factor pathway inhibitor:

Regulate inhibition by Fxa dependent inhibition of FVIIa-Tissue factor complex

during initial stage.

Function by binding the active site of Fxa and FVIIa-Tissue factor Via second and

first kunitz domain.

No co-factor requirement.

2)Antithrombin:

Serine protease type inhibitor.

Function by binding site of Fxa through exposed reactive center loop and

induces the conformational change which trap enzyme in inactive, stable complex.

Require co-factor ( Glycosaminoglycans).

Rezaie et al, biochemistry, 2002, 41, 6780


MECHANISM

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EXTRINSIC PATHWAY

FACTOR Xa

INTRINSIC PATHWAY

PHOSPHOLIPID

FVa-Fxa

Ca+

Direct

Factor Xa

inhibitor

Prothrombinase

complex

Prothrombin thrombin platelet

aggregation

fibrinogen fibrin clot

FXa


DISADVANTAGES OF CURRENT THERAPY

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General disadvantage of current therapy:

Slow onset of action

parenteral mode of administration

excessive bleeding

Stringent monitoring requirement

HEPARIN:

Parenteral administration.

Monitoring requirement.

Excessive bleeding.

WARFARIN:

Excessive bleeding.

Monitoring requirement.

Severe enzyme induction.

Advantages:

Low cost, Fast onset of action

Advantage:

Oral dose


PREFERREDPROFILE

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  • A wide therapeutic window of antithrombotic effect versus bleeding.

  • A rapid onset and offset of action.

  • Oral bioavailability

  • No coagulation monitoring required.

  • Inhibition of free and clot- bound thrombin.

  • Reproducible PK and PD profile.

  • Minimal interaction with food and other drugs.

  • Minimal dose frequency.

Weitz et al blood 2005 105 453

Hirish et al thromb res 2003 9 suppl 1:S1-8


COMPARISON OF ANTICOAGULANT

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NATURAL INHIBITORS

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Antistasis-

  • Isolated from extracts of mexican leech in 1987.

  • It is slow, tight binding, selective Factor Xa inhibitor.

  • Ki=0.3-0.6 nM.

TAP-

  • A single 60 amino acid peptide isolated from extract of tick.

  • Reversible, slow, tight binding inhibitor of Factor Xa.

  • Ki=0.5 nM.

Ghilanten-

  • Isolated from south American leech.

Simpson et al, j. biol. Chem, 1989, 264, 16694

Waxman et al, science,1990, 248, 593


S1 POCKET

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Most important pocket for binding for substrate or inhibitor.

Formed by 214-220 and 189-195 loops tied together by CYS 220- CYS 191

Disulfide bond.

Residues 225-228 form the base and lower strand of pocket.

Important residues are ASP 189, ALA 190 and GLN 192.

Rai et al current med chem, 2001, 8,101


S2 POCKET

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A small pocket merged with S4 pocket.

Likely this pocket defines the selectivity of selective Factor Xa inhibitor over thrombin.

Rai et al current med chem, 2001, 8,101


S3 POCKET

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Located on the rim of S1 pocket.

Most of Factor Xa inhibitor do not interact with this region.

Rai et al current med chem, 2001, 8,101


S4 POCKET

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S4 and S1 pocket represent the important binding region.

It is large and well defined pocket.

S4 pocket the 3 sub-regions:

Hydrophobic box

Cationic hole

water site

Hydrophobic box composed of Phe 174, Tyr 99, Trp 215.

Cationic hole is formed by Glu97 and Lys96.

Water is trapped underneath the Thr98, Ile175, thr175.

Rai et al current med chem, 2001, 8,101


TREND IN Fxa INHIBITORS

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Factor Xa inhibitors can be divided into three fragments:

P1 Group: Binds in the S1 sub-pocket.

Central Scaffold: project the substituent's into sub-pocket.

P4 Group: Binds in the S4 sub-pocket.

P1 group is further divided into 3 types:

- Highly Basic Group.

- Moderately Basic Group.

- Neutral Group.

Scaffold is further divided into 2 types:

- Flexible Scaffold.

- Rigid Scaffold.

Maignan et al. Curr. Top. Med. Chem. 2001, 1, 161


HIGHLY BASIC P1 GROUPS

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  • -salt bridge with Asp189

  • H-bond with Gly219

  • Poor bioavailability

  • 10 fold increased potency

  • -Enhanced oral absorption

Benzamidine

Napthyl amidine

-Similar inhibition constant

-Enhanced oral absorption

-4-fold more active than benzamide series

Amidino thiophene

Amidino indole


MODERATELY BASIC P1 GROUPS

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Form water mediated interaction with Asp189

Form H- bond with Gly219

10 times better at crossing Caco-2 monolayer than benzamidine

Amino isoquinolines

Similar pharmacokinetic activity and binding mode as amino isoquinolines

Aza indole


NEUTRAL P1 GROUP

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-Introduced by Lilly pharm.

-17-fold lower inhibition

-Improved Pk profile

-6-fold increase in potency

-Efficacy same as benzamidine

Chloro phenyl

Methoxy benzoyl

Chloro thiophene

Chlorothiophene


LINKER SCAFFOLDS (FLEXIBLE)

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Aliphatic chain

Amide bond

Amide ester

- To remove chiral center

- Gain H-bond to Gly219

- By Daiichi Pharm.

  • By Aventis Pharm.

  • Increases potency by 9 fold

  • Increases selectivity by 5 fold

  • Ester group located in small hydrophobic pocket

Allyl linker

Sulfonamide

Pentanoic acid

-Designed to circumvent chiral center


LINKER SCAFFOLDS (RIGID)

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Sulfonamido pyrrolidinone

Ether link

Cyclo heptanonediene

Cyclic urea

By Aventis pharm.

Potential for additional interaction.

By Berlex.

Photochemical liable

By Berlex

Optimal linker

By DuPont

H- bond with Gly216

Benzimidazole

Carbazole

Benzoxazinone

By Berlex

To add hydrophilicity

Introduced by Pfizer

By Berlex

To add hydrophilicity


P4 GROUPS

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Methoxy benzene

Amido diphenyl

By Lilly Pharm.

Phenyl lies parallel to Trp215

mM potency

Phenyl sulfonamide

Additional H-bond with Gly219

Pyridyl piperidine

By DuPont Pharm.

Edge to face with Trp215

OH interact with Tyr99

To increase hydrophilicity

Pyridine stack with Trp215

H-bond with structural water

Benzyl sulfonyl

piperidine

Amido benzofuran

Methoxy naphthalene sulfonamide

Phenyl imidazoline

Sulfonamide has conformational role

Edge to face interaction with Trp215

Piperidine play no role

Parallel to Trp215

By Berlex

Both ring are parallel to each other and perpendicular to Trp215

H-bond with Asn97


DRUGS AND THEIR CURRENT STATUS:

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RIVAROXABAN(BAY-59-7939)

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  • Oral , direct Fxa inhibitor under development.

  • It is oxazolidinone derivative.

  • IC50=21nM.

  • Currently in Phase III of clinical trail.

  • If approved , it will be marked by name Xarelto.

  • It is joined product of Bayer and ortho-McNiel pharmaceuticals.


SAR OF RIVAROXABAN

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1

IC50= 120nM

2

IC50= 8nM

3

IC50= 20μM

4

IC50= 90nM


SAR OF RIVAROXABAN

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Roehrig S, Straub A, Pohlmann J, et al. J. Med. Chem.48 (19): 5900


SAR around the aryl moiety

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R1 R2 R3 ent IC50 [nM]

H , H s 4.0

H , H s 0.7

F , H s 1.4

CF3, H s 1.O

NH2, H s 2.5

H , CH3 s 1260

H , H R 2300

R1 R2 R3 ent IC50 [nM]

F , H s 90

F , H s 32

H , H s 43

F , H s 40

H , H s 74

F , H s 140


Modifications on the amide linker and thiophene moiety

R1 X R2 IC50 [Nm]

CO H 2000

CO H 8.5

CO H 290

CO H 29

CO H 94

CO CH3 197

SO2 H 1200

R1 X R2 IC50 [Nm]

CO H 0.7

CO H 0.4

CO H 9.2

CO H 26

CO H 20

CO H 1170

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SYNTHESIS OF RIVAROXABAN (SCHEME I)

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Bayer healthcare Drug Fut 2006, 31, 484


SYNTHESIS OF RIVAROXABAN (SCHEME I)

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Bayer healthcare Drug Fut 2006, 31, 484


SYNTHESIS OF RIVAROXABAN (SCHEME II)

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Bayer healthcare Drug Fut 2006, 31, 484


Crystal structure
CRYSTAL STRUCTURE

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MAJOR BINDING COMPONENT

1. Hydrogen with Gly219

2. L-Shape provided by oxazolidine

3. Carbonyl doesn’t interact

4. Chlorine-Tyr228 interaction

Bayer healthcare, J. Med. Chem, 2005, 48, 5900


PHARMACOKINETIC PROFILE

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ABSORPTION AND DISTRIBUTION:

Peak plasma conc. is reached in 2 to 4 hours after oral administration.

Bioavailability range from 60-80%.

Presence of food increases maximum conc., time to maximum conc.

and AUC.

Bound extensively to protein (90%).

No effect of increased gastric pH on PK-PD profile.

METABOLISM:

Hepatic metabolism Via cytochrome P-450 3A4.

EXCRETION:

Both renal and hepatic excretion.

36% of drug is excreted unchanged in urine.


PHARMACOKINETIC PROFILE

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EFFECT OF AGE:

AUC was higher in patient above 75 years.

EFFECT OF RENAL INSUFFICIENCY:

AUC was 44%, 52%, 64% higher in mild, moderate and severe

renal insufficiency.

Still no recommendation in dose adjustment for renal insufficiency.

EFFECT OF HEPATIC INSUFFICIENCY:

With mild hepatic disease, no difference in PK-PD profile.

With moderate hepatic insufficiency, decrease in total body

clearance.

Patient with severe renal failure are excluded from clinical trails.

EFFECT OF OBESITY:

Compared in different weight group (<50, 50-80, 80-120, >120).

In higher Wt. group, AUC and inhibition was lower.

In lower Wt. group, Cmax was higher and half life was 2 hour longer.

EFFECT OF GENDER AND RACE:

No difference in PK-PD was found between the gender.


APIXABAN

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Apixaban is follow-up compound of razaxaban, a direct Fxa inhibitor.

Highly selective and potent (Ki=0.8nM) inhibitor of both free and bound Fxa.

It is product of Bristol-Myers Squibb (BMS).

CURRENT STATUS:

1). Phase III for VTE prevention study.

2). Phase III for prevention of stroke.

3). Phase III for other thromboembolic events in patient

with atrial fibrillation.


SYNTHESIS OF APIXABAN

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4

2

1

3

5

6


CRYSTAL STRUCTURE

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PHARMACOKINETIC PROFILE

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ABSORPTION AND DISTRIBUTION:

Apixaban is rapidly absorbed, Cmax in 1 hour.

Oral bioavailability is 80%.

Average half life is 12 hours.

METABOLISM:

70% of drug excreted unchanged.

CYP3A4 may be involved in metabolism.

EXCRETION:

60% excreted by fecal route.

25% excreted in urine.

Minor route of excretion is biliary.

Zhang et al, Drug. Met. Disp. 2008 (in press)


DO FACTOR Xa RELATE WITH CANCER??

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  • Cancer patient have elevated level of coagulation abnormalities.

  • Thrombosis is most frequent complication and 2nd leading cause of death in cancer.

  • Factor Xa, thrombin and tissue factor contribute to tumor growth.

  • Factor Xa promote tumor growth in 2 ways:

  • Fibrin provide network for growth and block access of immune system.

  • Recognition and binding to tumor cell to initiate cellular event.

  • Heparin suppress small cell lung cancer and B16 melanoma cell growth in animals.

  • Antistasin suppress T241 sarcoma cell growth in mice.

  • Ghilanten also suppress B16 melanoma cell growth in mice.

  • DX-9065a shown to inhibit A549 lung adenocarcinoma cell proliferation.


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