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CALIXARENES FOR DRUG DESIGN
HANNOVER MESSE-2007
16-20 April, 2007
Hannover
Iurii MATVIEIEV
+38 044 551-1628
+38 050 501-1393
[email protected]
National Academy of Sciences of Ukraine
Institute of Organic Chemistry
Institute of Bioorganic Chemistry and Petrochemistry
Palladin Institute of Biochemistry
Kiev
1
Talk outline
1.
2.
3.
4.
5.
6.
7.
8.
What is needed in the market?
Brief technology description.
Stage of development.
Who needs it & how many will they need?
What is my unique technology advantage?
Competitive matrix.
How will I beat the competition?
Opportunity for joint work.
2
Proprietary information statement
• The technology material presented in this talk is
available for licensing or joint product development.
• None of the slides contain any confidential or
proprietary information which would prevent patenting
the technology.
3
Problem Description & Market Need
(What is the problem? Or, What is needed in the market?
And, How big is the potential market? What is the disease
(if it’s a medical talk)? )
•
•
Inhibition of enzymes catalyzed phosphoryl transfer reactions is of
significant current medical interest since these enzymes regulate a
number of important biochemical pathways. The importance of these
enzymes allows to consider them as prominent targets for inhibitor
design. Of particular interest is of inhibition of alkaline phosphatases
involved in hormone signalling, tissue mineralization, tissue
inflammation and other biological processes.
Calcium ions are considered as universal second messengers that play
an important role in electrical and pharmacological coupling in
smooth muscles. Electrical or pharmacological stimulation of smooth
muscles during the excitation/contraction cycle changes the
concentration of Ca2+ in myocytes, which is regulated by systems of
energy-independent (passive) and energy-dependent (active) transport
of these cations.
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Brief technology description
• Calix[4]arenes substituted with
different
pharmacophoric
groups have shown multifarious
biological
activity
highly
diverse biomedical applications
of these molecules now include
antiviral,
anti-thrombotic
activities, enzyme blocking and
protein complexation.
• For
example,
the
preorganization of phosphonic
acid
fragments
on
the
calix[4]arene platform results in
a significant increase in the
inhibition
of
alkaline
phosphatase
Enantioselective Inhibition
of Porcine Kidney Alkaline Phosphatase
by the Chiral Aminophosphonous Acids
Inhibition
Constants, μM
Inhibitor
O
HO
HO
P
R
H
73
NH2
O O O O
H Pr
Pr H
O
H P(OH)2
O
(HO)2P
NH2
2.28
S
32
RR
1.7
H
H2N
O O O
H Pr
Selectivity
50.5
O
Pr H
SS
86
Organic Lett. 2006. 8. 549-552
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Advantages
(What is my unique and overwhelming technology advantage?)
Calixarenes are promising scaffolds for design of
inhibitors containing of bioisosteric groups – the medicinerelevant molecules. For example, effective inhibition of
alkaline phosphatases is of significant interest since these
enzymes catalyze the hydrolysis and transphosphorylation
of phosphate monoesters.
• The calixarene-methylene-bis-phosphonic acid is one of
the most efficient substance among the alkaline
phosphatase inhibitors described in the literature.
• Calixarenephosphonic acids in concentration 100µM
inhibit enzymatic activity of Na+, K+-ATPase by 86-98%
and don’t practically affect activity of Mg2+, ATPase.
•
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Experimental results
•
Calix[4]arenesulfonylamidines
influence Mg2+, ATP-dependent Ca2+
accumulation (Mg2+, ATP-dependent
calcium pump) in the myometrial
sarcoplasmic reticulum
In this case Ca2+ transport was
decreased by 75%. Calixarenephosphonic acids in concentration
100µM inhibit enzymatic activity of
Na+, K+-ATPase by 86-98% and don’t
practically affect activity of Mg2+,
ATPase. These calixarenes are more
efficient than ouabaine in suppressing
enzymatic activity of the sodium pump.
Calixarene Selective Inhibition
of Calcium Membrane Pumps
80
Inhibition, %
•
60
O S OO S O
O S O
O S O
N
N
N
N
F3C
CF3
CF3
F3C
NH
NH
NH
NH
40
20
0
-20
O O O O
1
2
3
4
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1. Mg2+,ATP-dependent Ca2+ accumulation in the miometrial sarcoplasmic reticulum.
2. Mg2+, ATP-dependent Ca2+ accumulation in the plasma membrane.
3. Ouabaine-suppressed Na+,K+-ATPase.
4. Mg2+,ATP-dependent Ca2+ accumulation in the mitochondria.
5. Ca2+-independent Mg2+-ATPase (“basal” Mg2+-ATPase).
Tetrahedron Lett. 2005. P.7459-7462
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Stage of development (clinical tests if medical) and
international patents
• A series of calixarene based alkaline phosphatase inhibitors
and Ca2+ exchange regulators were synthesized in the
Institute of Organic Chemistry NASU (see
www.ioch.kiev.ua/calix ).
• The high phosphatase inhibition activity and Ca2+
exchange regulation properties of the calixarenes were
studied in the Institute of Bioorganic & Petrochemistry
NASU and in the Institute of Biochemistry NASU (Org.
Lett., Vol. 8, No. 4, 2006, p.549-552; Tetrahedron Letters
46 (2005) 7459–7462).
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Targeted Market Segment
(Who needs it? How many will they need? What
price are they willing to pay, what do they pay now?)
• Bio-medicine Industry
• Pharmacology
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Competition
(Who is my competition? How will I beat the competition?)
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Competitive Matrix
Important product
or technology
characteristics
My company or
institute’s
product
Name of
Competitor #1
Name of
Competitor #2,
etc.
Key Characteristic
(a)
Key Characteristic
(b)
Key Characteristic
(c)
Key Characteristic
(d) (usually cost)
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Opportunities
(What I am seeking. Opportunity for joint work. Seeking
potential partners and licensees. And, How much will it
cost?)
We offer:
• The effective calix[4]arene based inhibitors
of alkaline phosphatases
• The effective Ca2+ exchange regulators
• Design of new biologically active
compounds by means of attaching of
pharmacophoric groups to the calixarene
platform
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Contact information
Iurii MATVIEIEV
+38 044 551-1628
+38 050 501-1393
[email protected]
Institute of Organic Chemistry
National Academy of Sciences of Ukraine
Kiev
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