MMV Sponsored Project :
Novel Oxaboroles for Potential
Treatment of Malaria
Jake Plattner
Anacor Pharmaceuticals
Anacor Pharmaceuticals: A Biopharmaceutical
Company Focused on Boron-containing Drugs
Two Proprietary Compounds in Late Stage Clinical Development
• Tavaborole: Topical Treatment for Onychomycosis – NDA filing 1H13
• AN2728: Topical Treatment for Atopic Dermatitis and Psoriasis – Phase 2
Key Strategic Corporate Partnerships
• Animal health R&D collaboration
• Anti-infective R&D collaboration
Prolific Boron Chemistry Platform
• 8 novel small-molecule compounds moved into development
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Why Boron?
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Boron has a Unique Bonding Orbital
Configuration: An Empty P-Orbital
Trigonal Planar

Boron has an empty P-orbital & can form a new bond under
specific conditions


Creates potential for differentiated bonding chemistry
The new bond forms a tetrahedral structure


Tetrahedral
Creates potential for new geometric interaction with target
Exploitation of P-orbital expands drug design possibilities
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Anacor Has a Strong Commitment to Neglected
Diseases
Research
Hit-to-Lead
Lead
Op
Preclinical
Safety
Phase
1
Parasitic Diseases
African Sleeping Sickness (HAT)
Visceral Leishmaniasis
Chagas disease
Malaria – Lead Series
Malaria (New Scaffolds)
River Blindness (Macrofilariacide)
River Blindness (Wolbachia)
African Animal Trypanosomiasis
Cutaneous Leishmaniasis
Bacterial Diseases
Tuberculosis (TB) LeuRS
TB new targets
Shigellosis (Bloody Diarrhea)
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Anacor’s Boron Chemistry Technology Has
Been Highly Productive (10 years)
Antitrypanosome
Antifungal Phase 3
Phase 1
Human African
trypanosomiasis
Onychomycosis
Antimalarial
Advanced lead
Antitrypanosome
Preclinical Candidate
Animal African
trypanosomiasis
Boron Chemistry
Technology
• In vitro screening
Me
Nmodeling
C
• Computer
Cl
• X-ray crystallography
O
O
Cl
OH
B
O
TB
Advanced lead
O
B
OH
N
OH
Me
B
O
Cl
-Lactamase
Inhibitor
Antibacterial
Preclinical
Gram-negative
bacterial infections
Phase 2
Gram-negative bacterial
infections/CF/Melioidosis
Anti-inflammatory
Phase 2 Atopic dermatitis
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Current Issues in Malaria Drug
Development
Epidemiology:
1. A child dies every 45 seconds of malaria
2. Half a billion new cases each year with
1-3 million deaths per year – mostly children
3. In endemic areas 50% hospital admissions
are for malaria
4. Significant resistance – even emerging
against artemisinins
Key Needs:
 Novel compounds with novel targets to overcome resistance
 Simple to use (1-3 doses) oral administration
 Low cost of goods – prefer < $0.50 - $1 per treatment
 Excellent safety profile for children and pregnant women
Ideally Also:
 Transmission blocking
 Radical cure – P. vivax
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Screening of Oxaboroles at UCSF, GSK and WRAIR
Resulted in Prioritization of 3 Anti-malarial Scaffolds
In vitro single point screen of
oxaborole library then IC50
In vitro
P. falciparum
7-Carboxy ethyl
benzoxaborole
O
6-Phenyl
benzoxaborole
6-Phenoxy
benzoxaborole
OH
OH
O
X
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OH
B
O
B
O
HO
O
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Oxaborole AN3661 Was Stopped in Pre-clinical
Development Due to Adverse Toxicology Finding

Highly potent biological effects
– In vitro IC50 = 20-56nM (including resistant strains suggesting a novel
mechanism)
– In vivo ED90=0.3 mg/kg (P.berghei); ED90=0.58 mg/kg (P. falciparum)
– In vivo cure at 10 mg/kg BID (4-days treatment) in mouse

Large safety margins in chronic toxicology studies
– > 300-fold
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Human dose and half-life predictions
– 15 mg per day (3xED90 once per day dosing for 3 days)
– 10 -12 hour half-life; Human once daily dosing predicted

AN3661 development stopped due to positive in vivo micronucleus
finding
AN3661
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Two Scaffolds, 6-Carboxyphenyl and 6-Carboxyphenoxy
Benzxaboroles, Represent Promising Leads
AN5961 (cyan)
IC50 = 560 nM (3D7)
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AN3330 (green)
IC50 = 1.1 M (3D7)
Key attributes for hit compounds:
– Low energy conformations show good overlap: hitting same target?
– Potent in vivo efficacy
• AN5961 cures at 100mg/kg BID (modified Peter’s Test)
• AN3330 ED90=11mg/kg BID (Peter’s Test)
– Good PK: Mouse t1/2 = 3-4 hr, F%>80, excellent exposure
– Negative in the in vitro micronucleus and Ames assay (AN5961)

Focus of lead optimization: Improve potency and increase t1/2 to
achieve single dose cure
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SAR Studies Identified AN9271 as an Advanced Lead
O
4’
HO
3’
A
2’
Cl
1’
B
OH
B1
O
3
AN9271
AN9271
IC50 =IC90
nM (3D7)
50 = 90 nM (3D7)
67nM (W2)
Avg=42nM vs 12 Ugandan isolates
In vivo ED90= 2.8 - 7 mg/kg BID/QD
Summary of SAR to date
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45 analogs in bi-phenyl series have been prepared to date
2’ position is hot spot: Cl >CF3 > F >H
In general, 3’-COOH and 4’-COOH substituents are comparable
Heteroatoms in ring A are tolerated
Halogens on ring B at 5-position reduce potency
PK of this series is good
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Excellent Oral PK for AN9271
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Ongoing Work to Improve Potency and t1/2 is
on Track to Discover a Late Lead by Q4/2013
Explore additional
2’-substituents
Introduce 7-halo or
Me to improve PK
Bioisosteres
& prodrugs of
carboxyl group
2’
7
1
6’
6
3
Add 6’-substituent to
assess 2’,6’-disubstitution
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Acknowledgements
Anacor Pharmaceuticals
– Yong-Kang Zhang
– Yvonne Freund
– Yasheen Zhou
– Eric Easom
– Virginia Sanders
– Vic Ciaravino
 Medicines for Malaria Venture
 UCSF
– Philip Rosenthal
– Juri Gut
– Ebere Sonoiki
– Sumit Rathmore
– Denghui Guo
 GlaxoSmithKline
– Laura Sanz
– F. Javier Gamo
– Brice Campo
– Emilie Burlot
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