New Compounds for Spinal Muscular Atrophy
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New Compounds for New Compounds for Spinal Muscular AtrophySpinal Muscular Atrophy
Jill Heemskerk, PhDJill Heemskerk, PhDOffice of Translational ResearchOffice of Translational Research
National Institute of Neurological Disorders and StrokeNational Institute of Neurological Disorders and Stroke
Jill Heemskerk, PhDJill Heemskerk, PhDOffice of Translational ResearchOffice of Translational Research
National Institute of Neurological Disorders and StrokeNational Institute of Neurological Disorders and Stroke
CONFIDENTIAL
Why NIH Chose SMA for a Drug Development Pilot
Urgent unmet medical need Urgent unmet medical need • Number one genetic killer of infantsNumber one genetic killer of infants
• Incidence: 1 in 6000 live birthsIncidence: 1 in 6000 live births
• No available treatmentsNo available treatments
Scientific opportunityScientific opportunity• Known cause = loss of SMN1 geneKnown cause = loss of SMN1 gene
• Defined treatment strategy: increase SMN2 Defined treatment strategy: increase SMN2
• Compounds identified that increase SMN2 in vitroCompounds identified that increase SMN2 in vitro
Urgent unmet medical need Urgent unmet medical need • Number one genetic killer of infantsNumber one genetic killer of infants
• Incidence: 1 in 6000 live birthsIncidence: 1 in 6000 live births
• No available treatmentsNo available treatments
Scientific opportunityScientific opportunity• Known cause = loss of SMN1 geneKnown cause = loss of SMN1 gene
• Defined treatment strategy: increase SMN2 Defined treatment strategy: increase SMN2
• Compounds identified that increase SMN2 in vitroCompounds identified that increase SMN2 in vitro
Indoprofen: Starting Point for Medicinal Chemistry
Indoprofen increases SMN protein in vitro:• SMN reporter assay
• SMN protein in patient fibroblasts
Indoprofen improves in utero survival of SMA mice
N
O
OH
Me
O
-B. Stockwell: Lunn et al, 2004
Optimizing Indoprofen for SMA
N
O
CH3
O
OH
Lactam Phenyl Acetic Chain
Substitutions: alkyl, halo, methoxy,
cyano, amino, aryl, heteroaryl
Substitutions: alkyl, halo,
methoxy, aryl, heteroaryl
Varied at methyl site,
length of chain, and
CO2H
Varied heterocycle
Chemistry Goals
Increase potency
Eliminate toxicity
• Cox Inhibition
Improve BBB penetration
Chemistry Goals
Increase potency
Eliminate toxicity
• Cox Inhibition
Improve BBB penetration
Benzo
CONFIDENTIAL
Chemistry Improves Potency and Activity
~1300 Indoprofen analogs synthesized and tested
Log concentration (µM)
lu
min
esce
nce
-6 -5 -4 -3 -2 -1 0 10.8
1.0
1.2
1.4
1.6
1.8
2.0
IndoprofenP407923
CONFIDENTIAL
ex6 ex8ex7 LuciferaseAndrophy/ZhouSMN-2 reporter assay
-AMRI
Untreated 5mM VPA 100nM SP869
SMA Project Compounds Increase SMN-containing Gems in Patient Fibroblasts
M. Lorson,University of MissouriConfidential
Pt C D Pt C D
Actin
SMN
1 2 3
0.0
0.5
1.0
1.5
2.0
2.5
CarrierDMSO
PatientDMSO 0.1 uM Drug
SM
N:A
ctin
SMA Project Compounds Increase SMN Protein in Patient Fibroblasts:Western Blots
Patient
Brenda Fung, CombinatoRxCONFIDENTIAL
SMA Project Compounds Stimulate Translational Read-through
-Courtesy Ellen Welch, PTC Therapeutics
UGA
+ Compound
- Compound
LuciferaseActivity
AUG UAA
Stop codon interrupts Luciferase:
CONFIDENTIAL
Positive Control
Indoprofen
-E. Welch, A. Bhattacharyya PTC Therapeutics
SMA Project Compounds Induce Translational Read Through
CONFIDENTIAL
Indoprofen Chemical Analogs are Drug-likePK: Good brain penetrance Orally bioavailable Rodent half lives around 2 hours Excellent human microsome stabilityTox: Well-tolerated in rodents (up to 50mg/kg, neonatal mice, 14 day dosing) Favorable CYP, genotox, hERG, broad target profiles Abolished Cox inhibitionIP: 2 NIH patentscover composition of matter
Half-life
Efficacy
Potency
Safety
ChemistryIP
Brain/Plasma
Pharmaceutics
CONFIDENTIAL
SMA ProjectFLOW PLAN
Candidate
August2010
Confidential
Timeline to Phase I Clinical Trial
3Q ‘10 1Q’114Q’10
28-Day GLP Tox
Formulation Development
2Q’11
ADME
GMP Synthesis
Safety Pharmacology
First in Human Trial
GLP Synthesis
3Q’11
Regulatory Submission
Radio Synthesis
14-Day GLP Tox
Dose Ranging Tox
200gm Synthesis
CONFIDENTIAL12
Acknowledgements Lead Development
John McCall Graham Johnson Paul Pearson Keith Houck Tony Bannon
NINDS Amelie Gubitz
SAIC Sabina Robinson Jim Romano
CombinatoRx Jane Staunton Brenda Fung Yang Wang Shakira Olanrewaju
AMRI Albany Keith Barnes John Lippert Nick Mayhew Ping Chen Steve Steffke Michelle Pilato
AMRI Bothell Svetlana Dobritsa Michelle Luche Sangeeta Chitnis
RTI Jim Matthews Ronnie Maitra Kimberly Ehman
Lorson Lab Chris Lorson Virginia Mattis Monique Lorson
PTC Therapeutics Ellen Welch Nikolai Naryshkin Sergey Paushkin Anu Bhattacharyya
Key Contributions Elliot Androphy Jianhua Zhou Brent Stockwell Charlotte Sumner Arthur Burghes Glenn Morris Meg Winberg Jill Jarecki
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