1. From
Chemistry
to
Drug Candidates

2. Agenda
• Introduction of Mercachem
• Drug Discovery & trends
• Development of services of Mercachem
• Project examples
1

3. Facts and figures
Innovative Netherlands-based chemistry service provider in
discovery chemistry, medicinal chemistry and process research
One of the leading CRO’s in Europe
110 employees (45% Ph.D. and 55% M.Sc./B.Sc.)
Spin-out of University of Nijmegen
Founded in 1997

4. Facts and figures
4,000 m2 modern research facilities with 10 synthesis
laboratories (120 fume hoods)
Moved to a new state-of-the-art laboratory facility in 2006
Located in Nijmegen (2 sites)
Independent, privately owned

5. Services
Exclusive
- Discovery chemistry services
- Medicinal chemistry services
- Process research & development services
to support research and development programs of
companies and research institutes worldwide
Regions:
- Europe
- US
- Japan

6. Markets
Pharmaceuticals (~70%)
Agrochemicals (~10 %)
Animal Health (~5%)
Flavors and fragrances (~5%)
Speciality chemicals (~5%)
• cosmetics
• monomers
• diagnostics
Research organizations (~5%)

7. Drug Discovery
Definition: process by which drugs are discovered and/or designed
Process:
• Identification & validation of target & candidates
• Synthesis, optimization & characterization
• Screening and assays for therapeutic efficacy
• Drug development
• Clinical trials
Despite advances in technology and understanding of biology
drug discovery is still:
• Lengthy, expensive, difficult, and inefficient process
• Low rate of new therapeutic discovery
Currently:
Research and development cost of each NME: ~ US$1.8 billion

8. Drug Discovery pipeline
Costs (m$)
(Out of pocket)
Costs (m$) 8
(capitalized)

9. Drug Discovery pipeline
UMC UMC
Mercachem
Synthon
Former Organon

10. Trends in pharmaceutical research
Mergers and acquisitions at big pharma
(Organon, Schering-Plough, MSD)
R&D is moving from big to medium to small specialized
companies
Outsourcing of R&D is increasing
- Total value: 15-24 billion$
- Increase: 10-20% per year
Increasing parts of drug discovery are being outsourced
Virtual pharma
Open innovation
10

11. Outsourcing
Reasons:
• Focus on primary activities
• Expertise
• New methodologies / technologies
• Cost effective
• Fasten product development (time to market)
• Capacity & Quality
11

12. Development of Services
Phase 0: Start
Start of Mercachem
• Two founders with PhD in Organic Chemistry
• Market trend for outsourcing and specialized companies
• Market niche for chemistry outsourcing
• Business plan, financing
• Start (1997)
Characteristics:
• Independent
• Professional
• Pragmatic
• Product & services according to market needs
• Compete on quality and innovation
12

13. Development of Services
Phase 1: discovery chemistry
Market trends (1996-2001):
• Outsourcing of small parts of drug discovery
• Outsourcing of non-IP projects
• Limited outsourcing of biology
• Pharma company in charge & initiates projects
13

14. Development of Services
Phase 1: discovery chemistry
Discovery Chemistry Services:
Lab-scale synthesis of:
• Research compounds
• Scaffolds and building blocks
• Reference compounds and metabolites
• Synthesis of compound libraries
• Development of novel chemistries
Project Goals:
• Preparation of (new) molecules for testing
• Method of preparation is not important
14

15. Drug Discovery pipeline
Discovery chemistry

16. Development of Services
Phase 2: Process R&D services
Market trends (2002-2005):
• Outsourcing of bigger parts of drug discovery
• Outsourcing of more IP sensitive projects
• Increasing outsourcing of biology
• Pharma company in charge & initiates projects
• Upcoming competition from low-cost countries
• Decreasing nr of new drugs entering the market
• Patent cliffs
• Mergers & acquisitions (M&A)
• Increasing need for innovation
16

17. Development of Services
Phase 2: Process R&D services
Process Research Services:
• Route development and route scouting
• Process optimization and catalyst screening
• Scale-up and small bulk supply
(~1 kg, non-GMP)
Project Goals:
• Candidate or lead molecule is known
• Development and optimization of
method of preparation
• Method development & Scale-up for
material supply regarding clinical studies (GMP)
17

18. Drug Discovery pipeline
Discovery chemistry
Process R&D

19. Development of Services
Phase 3: Medicinal Chemistry services
Market trends (2006-2011):
• Outsourcing of complete drug discovery projects
• Outsourcing of IP sensitive projects
• Both pharma company and CRO in charge
• Both pharma company and CRO initiates projects
• Increasing competition from low-cost countries
• Increasing M&A
19

20. Development of Services
Phase 3: Medicinal Chemistry services
Medicinal Chemistry Services:
• Hit Finding , Hit optimization
• Hit-to-Lead
• Lead Optimization
• ADME
Project Goals:
• Design of molecules based on target information
• Preparation and optimization of molecules with the right
properties
• Screening compounds against their properties
• Combination of chemistry and biology
20

21. Drug Discovery pipeline
Discovery chemistry
Process R&D
Medicinal chemistry

22. Integrated services
Target Assay Hit Lead Preclinical IND filing Phase 1
identification development finding optimization development
• Discovery Chemistry • Process chemistry
• Medicinal Chemistry
Skilled chemists
Knowledge
management Facilities/Equipment

23. Mercachem’s strengths
Unprecedented knowledge solving synthetic challenges by
team of experienced chemists and knowledge management
Creative and independent thinking complimentary to customer
knowhow
Strong communication skills and proactive attitude when
project requires
Reliability reaching success with respect to quality and time
High impact and high productivity due to combination of
creativity, proactivity and effective infrastructure

24. Performance in 2010
Number of active customers : > 60
Number of projects : 205
Number of compounds synthesized : ~ 4,500
Delivery rate : 98%

25. Patents and publications
Patents and publications:
• WO2009007098 (Syngenta)
• WO2009003650 (Bayer CropScience)
• WO2005019208 (Grünenthal)
• WO2004016581, WO2004074266 and WO2005028479 (Janssen)
• WO2003171374 (Johnson & Johnson)
• Synth. Comm., 2011, 41, 3246 (Janssen)
• Biorg. Med. Chem. Lett., 2010, 20, 4350 (MSD Newhouse)
• Eur. J. Org. Chem, 2010, 15, 2852 (Janssen)
• Tet. Lett., 2010, 51, 543 (Janssen)
• Synth. Comm., 2006, 36, 365 (Esperion)
• Biorg. Med. Chem., 2005, 13, 223 (Esperion)

26. Multidisciplinary Integration
Partnerships:
ZoBio Leiden
FBLG, NMR, Biacore
Proqinase Freiburg
Cancer pharmacology
Vichem Budapest
Kinase Inhibitor Library
Life Science Park Oss
Screening Facilities
(HTS, uHTS)
100.000 Library
28

27. Project Example:
Reverse Transcriptase inhibitors
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)
anti HIV-drugs
Collaboration between Janssen Research Foundation and Mercachem
In silico design
New molecules designed by molecular modeling.
X-ray crystallography of HIV reversed transcriptase complexed with key
analogues
Result: DAPY (DiArylPYrimidine) compounds

28. Project Example:
Reverse Transcriptase inhibitors
Project
Development & synthesis of 2nd generation DAPY compounds
Results
• 2 years of synthesis with a team of 3 chemists
• 280 compounds synthesized
• Several patents and publications (novel routes & compounds)
References
1. R. Leenders et al. Tetrahedron Lett. 2010, 51, 543 (patent: U.S. 7276510, 2007)
2. R. Leenders et al. Synth. Comm. 2010, accepted for publication (patent: WO 2005/028479)
3. R. Leenders et al. Eur. J. Org. Chem. 2010, 2852 (patent: WO2004/074266)
4. P. Janssen et al. J. Med. Chem. 2005, 48, 1901 (review)

29. Project Example:
Dr. August Wolff – Mercachem collaboration in Medicinal chemistry
Dr. August Wolff Arzneimittel GmbH & Co. KG and Mercachem BV
start two drug development collaborations
Bielefeld, Germany & Nijmegen, the Netherlands – August 26, 2010.
Dr. August Wolff GmbH & Co. KG Arzneimittel and Mercachem have
started two multi-year drug development collaborations.
Dr. August Wolff GmbH & Co. KG Arzneimittel have licensed a number of
patents from universities that cover novel classes of molecules with
potential use in dermatology. Mercachem is responsible for
medicinal chemistry and project management with the goal to
further improve the properties of these molecules and to develop
them into clinical candidates.

30. Project Example:
PDE inhibitors for Neglected Tropical Diseases
Project T4-302:
PDE inhibitors for Neglected Tropical Diseases
Focus: African Sleeping Sickness
Parasitic Disease (Trypanosome brucei)
100% fatal if untreated
50 million people at risk
Present Medication: A disgrace of modern pharmaceutical sciences
old and toxic (~10% patients die from side effects),
painful, resistance
Aim of T4-302:
A PDE (PhosphoDiEsterase) inhibitor as novel and well tolerated
medication for the African sleeping sickness
Lead compound
PDE

31. Project Example:
PDE inhibitors for Neglected Tropical Diseases
Project T4-302:
PDE inhibitors for Neglected Tropical Diseases
Mercachem:
• participates in TIPharma (Top Institute Pharma)
• project management, synthesis, SAR, medicinal chemistry
PARTNERS IN CONSORTIUM
• Mercachem, Nijmegen NL
• Nycomed Pharma, Zurich CH
• Top Institute Pharma
• Vrije Universiteit, Amsterdam NL
• University of Berne, CH
• IOTA pharmaceuticals, Cambridge UK
• Drugs for Neglected Disease initiative, Geneva CH
• Koninklijk instituut van de Tropen, Amsterdam NL

32. Project Example:
PDE inhibitors for Neglected Tropical Diseases
Volkskrant 13-09-2011

33. www.mercachem.com
Dr. Eelco Ebbers
eelco.ebbers@mercachem.com