Download GABA Receptor Agonists for Treatment of Bronchoconstrictive

GABAA Receptor Agonists for Treatment of
Bronchoconstrictive Disorders
(OTT ID 1319)
Inventors: Doug Stafford, Ph.D, James Cook, Ph.D. Alexander Arnold, Ph.D.
from the Department of Chemistry and Biochemistry, UW-Milwaukee
Charles Emala, M.D and George Gallos, M.D. from the Department of
Anesthesiology, Columbia University Medical Center
For further information please contact:
Jessica Silvaggi
Licensing Manager
1440 East North Ave.
Milwaukee, WI 53202
Tel: 414-906-4654
[email protected]
©UWMRF 2017
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5/18/17
Shortfalls of current drugs for asthma
Problems:
• Many patients are not successfully treated using the inhaled glucocorticosteroids and/or bagonists normally used in asthma
• Inhaled drugs are more difficult to administer, especially for children
• Corticosteroids take several weeks to become effective; benefits wear off quickly without
continued daily use
• Side effects of steroid drugs
Solution:
• The inventors have discovered novel small molecules selective for gamma-amino butyric
acid type A receptors (GABAAR) as a new drug therapy for bronchoconstrictive disorders
• Inventors have shown that these small molecule agents selectively agonize GABAAR to relax
contracted human or rodent airway smooth muscle (ASM)
• It has also been shown that inflammatory cells express functional GABAAR and can be
targeted with GABAAR ligands
• Various drug formulations are claimed in the patent application, including drug
compositions and their aerosol and oral formulations
©UWMRF 2017
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Road to Commercialization: Market, Intellectual Property, and Partnering
Market
•
•
•
•
The significance of asthma is reflected in an estimated global prevalence of 245 million persons, with
nearly 25 million afflicted in the US alone (about 8.2% of the population)
It is the most common chronic disease of children with disparate impact in US minority populations
High disease prevalence results in an estimated US health care cost burden of $56 billion (in 2007)
The global market for asthma and chronic obstructive pulmonary disease (COPD) prescription drugs
was valued at $34.9 billion in 2011
Intellectual Property
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•
Issued Patent, composition of matter alpha 5 compounds 7618958
PCT Patent Application WO 2014/047413
Partnering
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•
This technology is part of an active and ongoing research program and is seeking partners for
development of the final product
It is available for developmental research support/licensing under either exclusive or non-exclusive
terms
©UWMRF 2017
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RNA Expression of GABAAR α4 and α5 in ASM
•
Representative images of RTPCR products corresponding to specific GABAA subunits following
laser capture microdissection of airway smooth muscle cells harvested from human and guinea pig
tracheal airway smooth muscle. (bp = base pairs, ASM = airway smooth muscle, Hu = human, GP =
guinea pig, neg = negative, and pos = positive). Representative of 2 separate individual human or
guinea pig tracheas.
©UWMRF 2017
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In vitro binding affinity at αxβ3γ2
GABAA/benzodiazepine site subtypes
Compound
α1
α2
α3
α4
α5
α6
XHEIII-74
77
105.5
38.5
0.42
22
5.8
CMD-45
90.5
65.5
30.3
0.15
1.65
0.23
Li, X., Ma, C., He, X., Yu, J., Han, D., Zhang, C., Atack, J. and Cook, J. 2002. Studies in Search of DiazepamInsensitive Subtype Selective Agents for GABAA/Bz Receptors. Med. Chem. Res. 11(9):504-537.
• Lower numbers predict better binding at the site
• α6 is not present in the lung tissue
©UWMRF 2017
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Compounds exhibit selectivity for α4 or α6 GABAAR in oocytes
• Compounds exhibit functional selectivity bias in favor of α4 or α6 GABAAR. Selectivity is
quantified by dose-response curves showing greater inward currents (i.e. agonist
activity).
• Test compounds CMD-45 and XHe-III-74 were assayed using two electrode voltage
clamp measurements on Xenopus oocytes recombinantly expressing single α-subtypes
(in the GABAAR configuration of α(x)β3γ2)
©UWMRF 2017
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ASM express GABAA α4/α5 subtype and
are relaxed with compound treatment
Figure 1a. CM-D-45 or Xhe-III-74 activation of α4
containing airway smooth muscle GABAA
receptors induces direct relaxation of TEA
induced contractions.
CM-D-45 and Xhe-III-74, ligands specific for α4
subunit containing GABAA channels both induce
dose-dependent relaxation of guinea pig tracheal
rings contracted with the depolarizing stimulus
TEA but Xhe-III-74 demonstrates greater potency.
Data are expressed as percent of muscle force
remaining at 15 min after the addition of the α4
ligand to a sustained TEA contraction. (n=4); $$,
**=p<0.01 and ***=p< 0.001 compared to initial
tone. **=p< 0.01 and ***=p<0.001 compared to
CM-D45.
Guinea pig tracheal rings
©UWMRF 2017
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GABAA α4 subunit mediated relaxation for human ASM
Figure 1b. Xhe-III-74 demonstrates
greater potency at relaxing
acetylcholine (Ach)-induced
contraction of human airway smooth
muscle compared to 200 μM CM-D-45
or vehicle (0.1% DMSO.
Data is expressed as percent of muscle
force remaining at 15min after the
addition of the α4 ligand to a
sustained acetylcholine contraction). n
= 3-4. * p< 0.05 compared to vehicle
Human ASM
©UWMRF 2017
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GABAA α4 compounds induce inward
rectifying signals in human T cells
• Inflammatory cells such as T-lymphocytes and monocytes/macrophages also express
the α4 subtype, and activity of these cells can be suppressed by GABAAR modulating
agents
Figure 2: Membrane polarization effects of GABAA agonists CMD-45 and XHE(II)-074 on human Jurkat
E6-1 cells. Assays performed with the IonFlux patch clamp system (as described in ref. 11).
Inserts show inward rectifying currents (mA) at various doses. Compounds tested with 0.1 μM GABA.
Curves show average of four determinations at indicated doses and standard deviations.
©UWMRF 2017
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Activation of α5 GABAAR induces relaxation
Left: Representative force tracings from guinea pig tracheal rings pre-contracted with TEA.
Spontaneous and complete relaxation was seen following treatment with 50uM SF-053-2’-FR-CH3 (lower panel) compared to vehicle control (upper panel).
Right: Magnitude of relaxation achieved 30 minutes following treatment with 50uM SF-0532’-F-R-CH3. Expressed as remaining tension (in grams) between vehicle control treated baths
(left) and those receiving SF-053-2’-F-R-CH3 (right). * = p<0.05; n=4
©UWMRF 2017
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Summary
• A new target for asthma and bronchial inflammation has been identified in
the airway smooth muscle of the lungs
• Novel molecules have been designed to target the GABAAR α4 and α5
subunits in the lung
• These drugs will be designed not to reach the brain, but rather act
specifically only in the airways
• α4 and α5 specific GABAARs have been detected in the ASM
• Results show that α4 and α5 specific compounds can relax the ASM in
guinea pig and human models
©UWMRF 2017
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Next Steps: Further Proof of Concept
• In vitro Assays
– Subject lead compounds to battery of assays to establish druggability
• Novel Deuterated Compounds
– Synthesize and test additional novel deuterated compounds for efficacy
and druggability compared to current leads
• Animal Studies
– Mouse studies to look at safety information, PK, and efficacy by aerosol
and oral dosing
©UWMRF 2017
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5/18/17
GABAA Receptor Agonists for Treatment of
Bronchoconstrictive Disorders
(OTT ID 1319)
For further information please contact:
Jessica Silvaggi
Licensing Manager
1440 East North Avenue
Milwaukee, WI 53202
Tel: 414-906-4654
©UWMRF 2017
13
5/18/17