1 CALIXARENES FOR DRUG DESIGN HANNOVER MESSE April, 2007 Hannover Iurii MATVIEIEV National Academy of Sciences of Ukraine Institute of Organic Chemistry Institute of Bioorganic Chemistry and Petrochemistry Palladin Institute of Biochemistry Kiev

2 Talk outline 1.What is needed in the market? 2.Brief technology description. 3.Stage of development. 4.Who needs it & how many will they need? 5.What is my unique technology advantage? 6.Competitive matrix. 7.How will I beat the competition? 8.Opportunity for joint work.

3 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.

4 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 its 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.

5 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

6 Advantages (What is my unique and overwhelming technology advantage?) Calixarenes are promising scaffolds for design of inhibitors containing of bioisosteric groups – the medicine- relevant 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 dont practically affect activity of Mg2+, ATPase.

7 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%. Calixarene- phosphonic acids in concentration 100µM inhibit enzymatic activity of Na+, K+-ATPase by 86-98% and dont practically affect activity of Mg2+, ATPase. These calixarenes are more efficient than ouabaine in suppressing enzymatic activity of the sodium pump.

8 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 ). 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 ; Tetrahedron Letters 46 (2005) 7459–7462).

9 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

10 Competition (Who is my competition? How will I beat the competition?)

11 Competitive Matrix Important product or technology characteristics My company or institutes product Name of Competitor #1 Name of Competitor #2, etc. Key Characteristic (a) Key Characteristic (b) Key Characteristic (c) Key Characteristic (d) (usually cost)

12 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 Ca 2+ exchange regulators Design of new biologically active compounds by means of attaching of pharmacophoric groups to the calixarene platform

13 Contact information Iurii MATVIEIEV Institute of Organic Chemistry National Academy of Sciences of Ukraine Kiev