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Development of Innovative Medicines in Russian Academic Institutes. The Experience of Nonprofit Partnership “Orchemed” Prof. Sergey Bachurin, corresponding-member of Russian Academy of Sciences
Examples of innovative drug-candidates developed in the institutes of Russian Academy of Sciences
Zelinsky Institute RAS Harvard Medical School Chemical synthesis of conjugated vaccine against Staphylococcus aureus D-Glucosamine HO O 28 Chemical steps: Protective efficacy against HO HO O,N-functionalization, the infection of mice with H2N OH Introducing of spacer groups, methicillin-resistant HO O glycosylation reactions, Staphylococcus aureusHO O HO O Removal of blocking groups. (MRSA) strain H 2 N HO O HO O H 2N H O O HO O H 2 N HO O HO O H 2N HO O Oligosaccharide HO O H 2N H O O ligand L Conjugated vaccine HO O H 2 N HO O Survival (mice) HO O H 2N H O Without vaccine HO O H 2 N HO O HO O SH H 2N Protein- carrier (dTT) Conjugated vaccineCollaboration: Zelinsky Institute, RAS (chemical synthesis) and Harvard Medical School (bacteriology)Marina Gening, T. Maira, A. Kropec, D. Skurnik, Y. Tsvetkov, N. Nifantiev*, G. Pier* «Synthetic β(16)-linked N-acetylated and non-acetylated oligoglucosamines to produce conjugate vaccines for bacterial pathogens» Infect. Immun., 78 (2009) 764-772.
Institute of Physiologically Active Compounds RAS and Institute of Normal Physiology RAMS Development of new generation of memory-enhancers and neuroprotectors 703D-docking of binary AMPA-receptor modulators Restoration of weak or lost 60 * * memory in animal models 50 Avoidance % O 40 30 R2 N N 20 O O 10R1 Binary ligand of AMPA-receptor 0 Saline 5 min pre 5 min post 4h post modulation site Retention Training test 0 24 hours Wild-type Symptomatic TG TG + IP-0012Novel neuroprotectiveagents developed, whichblock proteinopathy indifferent animal modelsof neurodegeneration(TDP-43 protein andgamma-synucleintransgenic animals) Contractual work with Bayer AG, Pfizer, AC Immune (Switzerland)
Novosibirsk Institute Institute of Problem of Institute of Physiologically Institute of Organicof Organic Chemistry RAS Chemical Physics, RAS, Active Compounds, RAS Chemistry, RAS, Ufa (both from Chernogolovka, Moscow region) Development of novel generation of drugs on the basis of natural and synthetic nanosupports OH O O Clathrates of pharmacones with nano-matrixes HO O O O HO of plant origin – the new approach for O HO OH HO OH O increasing efficacy, bioavalability and HO O OH OH O O OH decreasing toxicity of known drugs O O HO OH HO «Symvaglysin» clathrate of simvastatin with glycyrrhyzic acid (GA)– new cholesterol- lowering agent (with ED reduced in 3 times). Clathrate of GA with allapenine – new safe anti-arrythmic more active and less toxic than medicine Allapenine, IOC Ufa (The above agents are approved for clinical trials) Original complexes of C60-fullerene and soluble polymers with known medicines (developed in IPCP and IPAC RAS) showed significantly improved pharmacological profile of these medicines.
Institute of Organic Synthesis (IOS, Ekaterinburg, Ural Branch RAS) Development and manufacture of highly-requested medicines for Russian pharma market ANTI-VIRAL AGENT «TRIAZAVERIN»:LISOMUSTIN laboratory to the marketa new anti-cancer agent Produced and NO certified more than 20 000 capsule H N N COOH Cl O NH2 NO H N N COOHCl O NH2 O OH F PEFLOXACIN N O N N H3CHighly efficient CH 3antibacterials in series offluoroquinolones with broadspectrum of biological activity. Broad spectrum of anti-virus activity (human andTechnology of its production is chicken influenza, PC-infection, vernaldeveloped encephalitis, etc). Clinical trials are under completion.
To consolidate the researches of academic institutes in the field of drug discovery the Nonprofit Partnership “OrCheMed” (Organic-Chemistry forMedicine) of more than 10 leading academic institutes was founded in 2005. It unites scientific and innovative potential of about 3000 scientists. 730 including 200 including 470 scientific personnel 110 scientific personnel INEOS RAS IPAC RAS 700 including (Moscow) (Chernogolovka) 300 scientific 1200 including > 600 personnel IOC RAS Ins.Probl. Chem. Phys. RAS scientific personnel (Москва) (Chernogolovka) 200 including Ins.Org. Synth. Ins.Org.Phys. 130 scientific Ural Branch RAS Chem. RAS 450 including 250 personnel (Ekaterinburg) (Kazan) scientific personnel IBOC RAS Ins.Org.Chem. 800 including (Moscow) RAS (UFA) 200 including 380 scientific 130 scientific personnel personnel Ins.Chem. Novosibirsk Inst. RAS (Rep. Komi) Org.Chem.RAS 180 including 450 including 130 scientific personnel 250 scientific personnel MISSION:•Analyzing of chemical compounds libraries, developed in different institutes.•Organizing of virtual and biological screening of chemical compounds libraries.•Providing the pharmacological and marketing expertise for hit-compounds developed in theinstitutes.•Foundation of novel start-up companies;•Development of nascent IP from consortium members through project funding and licensing.
Modern centers for preclinical trials in the Russian Academy of Sciences. Center for preclinical trials in Chernogolovka Siberian Center for animal genetic Laboratory forBioscreening models (Puschino Branch of the (Novosibirsk) Institute of Bioorganic Chemistry) • In vivo screening of active compounds • Toxicological and safety study of lead- compounds. • The full-cycle of preclinical trials
“Traditional” Drug Discovery Strategy «Nature Rev.Drug Disc.» 2004-2007 Drug discovery (R&D)Synthesis of Screening Hit- new Compounds Lead- (computationalcompounds and bio- optimization Compounds screening) optimization Pre-Clinical Trials (GLP) appr. 1 000 000 comp. (1000 comp.) (100 comp.) Drug-candidates Appr. 15 years (10) About US$ 1BL 1 PHASE (60-70% success) 3 PHASE 2 PHASE (40-60% success) (25-40% success) 1 DRUG CLINICAL TRIALS ON THE MARKET
“Orchemed” as a “catalyst” of drug discovery process in academician institutes NP “OrCheMed” Synthesis of Screening Hit- new Compounds Lead- (computational Centers for compounds and bio- optimization Compounds screening) optimization preclinical trials Pre-Clinical Trials (GLP) appr. 1 000 000 comp. (1000 comp.) (100 comp.) Drug-candidates (10) Medicinal chemistry approaches decrease time and cost of R&D stages 1 PHASE (60-70% success) 3 PHASE 2 PHASE (40-60% success) (25-40% success) CLINICAL TRIALS“Orchemed” should cover the “Nishe” of accumulation of chemical librariesdatebases and selection and commercialization of hit- and lead-compounds
Project portfolio Antiviral drug BG-122 (INEOS RAS) Anticoagulant LS-27 (IOS UrB RAS) Antineurodegenerative drug RU-32 (IPAC RAS) Antiinflammatory drugs (Yaroslavl SU) Antiparkinson drugs (IOC Novosibirsk) Portfolio: Cardiovascular drug Dibornol (IC Syktyvkar) >50 projects in Antitumor drugs (IOS, IPCP) actual Advanced drug delivery systems (IPAC, INEOS, pharmacologicalIPCP) areas etc. www.orchemed.com +7 (496) 524-2563
Recognized academic expert group • Invited experts for State Duma, government, mass media, etc. • Official codevelopers of Strategy of Development of Pharmaceutical Industry of Russian Federation in 2008-2020 (Pharma-2020) • Expert evaluation of work projects for business groups • Initiator of strategic national projects, such as National bioscreening network • Strategic partnership with Russian innovative (bio)pharmaceutical companies, biopharmclusters, etc. Presentation of Orchemed Participation in State Duma initiative Project ”National Presentation of Orchemed Committee WorkshopBioscreening Network” Projects to Minister E.Nabiulina in State Duma www.orchemed.com and ROSNANO Head A.Chubajs +7 (496) 524-2563
Model of commercialization IP rights Business partners Institutes NP Orchemed of RAS Royalties from • Binnopharm license agreements One of the biggest GMP start-up companies Startup-5 manufacturers in Russia Venture funds Startup-4 capital • Biopharmacluster (e.g., Russian Startup-3 investments Startup-2 BioCity venture company) Startup-1 or • Maxwell Biotech out-licensing Pharmaceutical • International fund of companies technology and Investment • Obninsk pharmcluster “Park of active Typical distribution of molecules” shares in start-up: • and many other Scientists-developers – 75% scientific and business organizations in Russia NP Orchemed – 25%www.orchemed.com and former USSR +7 (496) 524-2563
National Bioscreening Centers Network, NBCN (Project, developed jointly by RAS, RAMS, MSU and NP Orchemed) The main goals of the project (2010-2012): 1. Development and launch an integrated infrastructure of biological screening in Russia for providing discovery of novel innovative medicines. 2. Development of series (30-50) of highly efficient lead-compounds for the most requested fields of medicine and launch of 3-4 innovative drugs on Russian pharma market at 2020. Proposed Structure of NBCN
The most fundamental and lasting subject of synthesis is not production of new compounds, but production of properties. George S. Hammond. Norris Award Lecture, 1968 Drug Discovery – One of the Most Requested Field of Chemistry- In 2007, the global pharmaceutical market grew to US$712 billion (what is about 80% ofGlobal Oil Market).- Year-on-year the global pharmaceutical market increased to 10.7% in 2007, largely as aresult of strong sales for new innovative products and high market growth in emergingpharmaceutical markets such as China, India and Russia.- It is expected that the global pharmaceutical market is forecast to grow to US$929 billion in2012. The report “Pharmaceutical Market Trends, 2008 - 2012”According to the “Strategy of the development of Russian pharmaceuticalindustry till 2020”, approved by the Russian Government it is expected thatabout 30% of all drugs in Russian Pharma Market will be new innovativemedicines.Therefore one of the main line of activity of Russian Academy of Science isthe provision of fundamental scientific background for the development ofnovel promising drug-candidates.
Nonprofit partnership of chemical institutes of RAS «Orchemed» (Organic Chemistry for Medicine). General informationEstablished in 2005The legal status: nonprofit partnershipFounders: Institutes of RASManagement:Scientific Board (Chairman – Acad. N.S. Zefirov), Board of experts (Chairman – Corr. Member of RAS S.O. Bachurin), Director (K.V. Balakin, PhD, DSc)Institutes-members: 11 institutes of RAS: Institute of Physiologically Active Compounds,Institute of Problem of Chemical Physics, Institute of Organic Chemistry, Institute ofElementorganic Compounds, Institute of Bioorganic Chemistry (all from Moscow area),Institute of Organic and Physical Chemistry (Kazan), Institute of Chemistry (Syktyvkar),Institute of Organic Chemistry (Ufa), Institute of Organic Synthesis (Ekaterinburg),Institute of Organic Chemistry (Novosibirsk), Institute of Chemistry of Solutions (Ivanovo) www.orchemed.com +7 (496) 524-2563
Features Orchemed – Russian biggest cooperative academic initiative in the field of drug O O N O discovery and development HN HN N HN S N N N N O N O N O N Complete cycle of preclinical innovative drug Pirenzepine N Zolenzepine N Telenzepine N (Boehringer Ingelheim) (Byk Gulden) (Byk Gulden) discovery From virtual screening to preclinical animal studies Portfolio of innovative projects More than 50 projects in actual therapeutic areas Focus on innovative developments Distinctive feature of academic projects Orchemed’s Mission: To identify and promote prospective technologies developed in Russianacademic institutes, and pave the way to effective technology transfer to national and global www.orchemed.com pharmaceutical industry +7 (496) 524-2563
Drug Discovery: as a rate-limiting step in Drug Development In vivo testing and HTP-screening systems preclinical trials of lead-compounds O “Weak O N Link” ! Animal Video camera N Water pool Hidden N O (rat) N N + F F Platform CH3 F N N N N Focused chemical N N N N O N CH3N N O S H3C libraries N CH3 Chemical O N O S N S N N N N compounds Drug-candidates N N N N N N Cl libraries N N S S N N N O N OH O N H3C O N N N OH N O N O O Optimization of hit- and O + N CH3 lead- compounds Virtual prescreening
National Bioscreening Centers Network, NBCN (Project, developed by NP Orchemed jointly with RAS) Ufa The main goals of the project (2010-2012): Development and launching an integrated infrastructure of biologicalscreening in Russia for providing discovery of novel innovative medicines Development of series (30-50) of highly efficient lead-compounds for the most requested fields of medicine as a potential innovative drugs on Russian market at 2020.