Case study of a hit-to-lead optimisation and medicinal chemistry programme manage by Idealp-Pharma

1. Idealp-Pharma
Hits optimisation /
Leads identification /
Leads optimisation
Case study

2. Hits optimisation / Leads identification
Medicinal chemists, biologists and cheminformatics specialists work
closely together to accelerate your hits optimisation and leads
identification. You can pick up what you need to support your
project.
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3. Hits Optimisation / Leads Identification – Case Study
Biological Assay
Biological Assay
Primary screening test
Primary screening test
Analysis and validation of hits
Analysis and validation of hits
Classification by scaffolds
Classification by scaffolds
Chemical and biological validation
Chemical and biological validation
Optimisation by cheminformatics
Optimisation by cheminformatics
SLF Libmaker
SLF Libmaker
Pharmacophoric approach
Pharmacophoric approach
Chemistry
Chemistry
Synthesis, Chemical space exploration, Focused libraries
Synthesis, Chemical space exploration, Focused libraries
Chemical optimisation of hits
Chemical optimisation of hits
Early ADMET Tests
Early ADMET Tests
Solubility,
Solubility,
Plasmatic Stability, Metabolic Stability
Plasmatic Stability, Metabolic Stability
Identified Lead
Identified Lead
33to 66different famillies
to different famillies
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4. Hits Optimisation / Leads Identification – Case Study
Primary screening
We are equipped for and experienced in transferring primary
screening assays into our labs and assessing a compound’s
activity using in vitro methods and cell-based assays
including assay design and set-up. For cell-based assays, we
have built a bank of cell lines and we are able to cultivate
fibroblasts from different sources.
We are equipped with three microplate readers that allows all
type of detection including HTRF.
Typical project of screening project include:
- Screening transfer and validation
- Screening performance
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5. Hits Optimisation / Leads Identification – Case Study
A cheminformatics approach for hits analysis
In order to meet the medicinal chemists requirements, we
evaluate molecular diversity in terms of the scaffold and
not just the data descriptor.
Libraries can be screened in silico, docked and clustered
by scaffold to pick up the most likely hits for your target on
the basis of either a known pharmacophore or the active
site's 3D structure.
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6. Hits Optimisation / Leads Identification – Case Study
Measurement of physical-chemical properties
We can evaluate pKa and assess kinetic solubility and
stability. Our biology capabilities allow us to rapidly
assess solubility in medium and culture buffer for initial
biological hit validation
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7. Hits Optimisation / Leads Identification – Case Study
Cheminformatics
Our SLF-Libmaker® proprietary cheminformatics platform is
a powerful tool for speeding up the lead optimisation
process, in combination with docking and pharmacophore-
based approaches. We can design a combinatorial virtual
library using the scaffold of interest, linkers and functional
groups. The library's compounds are then docked onto the
target of interest to obtain hits with the best potential activity.
After post-processing and filtering parameters processes, the
end result is a good virtual hit ranking for assisting the
medicinal chemist.
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8. Hits Optimisation / Leads Identification – Case Study
Cheminformatics – SLF-Libmaker®
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9. Hits Optimisation / Leads Identification – Case Study
Cheminformatics – Published data
-9- Krier, M.; de Araujo-Junior, J. X.; Schmitt, M.; Duranton, J.; Justiano-Basaran, H.; Lugnier, C.; Bourguignon, J.-J.; Rognan, D.
J. Med. Chem.; (Article); 2005; 48(11); 3816-3822

10. Hits Optimisation / Leads Identification – Case Study
Cheminformatics – Hits optimisation case study
Objective: optimising a known lead by systematic
exploration of substituents around a core scaffold.
Realisation: Focused screening of small-sized libraries (< 500
compounds) on a macromolecular target for which hits/leads
have already been identified.
Competitive advantages: Our SLF_Libmaker® technology
ensures rapid, stepwise optimization of a known lead while
maximising the chances of obtaining better compounds at
each iteration cycle (design-enumeration-synthesis).
Average duration : 3 to 6 months
Required resources are measured in terms of FTEs
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11. Hits Optimisation / Leads Identification – Case Study
Medicinal chemistry
In each project, computational scientists, biologists and
chemists work together to choose the best building blocks,
particularly for synthetic accessibility and SAR studies. Our
medicinal chemists are experienced in generating SARs and
optimising ADMET properties on the basis of primary and
secondary screening results.
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12. Hits Optimisation / Leads Identification – Case Study
Chemistry – Optimisation projects
The majority of Idealp-Pharma’s business is derived
from exclusive, confidential, novel molecule synthesis
contract projects. Most client programmes require
flexible management of molecule optimisation
projects.
Expertise and background in particular chemistry
- Multi-step synthesis
- Boronic chemistry
- Steroid chemistry
- Carbohydrate chemistry
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13. Hits Optimisation / Leads Identification – Case Study
Chemistry - IP and chemical space evaluation
We can work with your scientists or managers to put their
ideas and inventions into a format that will facilitate the
patenting process. With our analogues synthesis capabilities,
we can specially focus a synthetic programme on patent
protection and expansion
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14. Hits Optimisation / Leads Identification – Case Study
Chemistry – Hits optimisation case study
Objective: optimized hits / identified leads belonging to 3 to 6
different chemical families
Realisation : Idealp-Pharma performed an iterative process as long
that one can find commercially available pertinent (i.e. useful for
building Structure Activity Relationships) analogues including:
- Analysis of hits
- Search of analogues in our virtual 1.6 million compounds library
- Purchase of available compounds and preparation of plates
- Synthesis of focused libraries
- Chemical synthesis for space exploration
- Chemical optimisation of hits
Duration: 9 months after the identification of hits for 3 to 6 chemicals
families (average size of families 15 to 20 compounds)
Required resources are measured in terms of FTEs
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15. Hits Optimisation / Leads Identification – Case Study
Exploratory in vitro ADMET
Our exploratory in vitro ADMET capabilities allow us
to perform on-site permeability assays (PAMPA), metabolic
and plasmatic stability on human and murin microsomes,
CYP450 inhibition and cytotoxicity tests (MTT, ATP and
LDH release tests). All chemistry, computational approach,
screening and ADMET data and results are discussed by our
project team and made available to our customers. The aim
is to turn validated hits into candidates to in vivo
evaluation.
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16. Hits Optimisation / Leads Identification – Case Study
Exploratory in vitro ADMET - Case study
Medicinal chemistry
IC50 < ynM BTMC*
Cytotoxicity
IC50/CYTOTOX < 0.1
Other in vitro tests
BTMC* Ok
Ames Solubility tests Plasma stability PAMPA
Non OK Non OK Ok Ok Non OK
BTMC* BTMC*
BTMC* Non OK Ok
Exploratory Exploratory
PK sc PK per or
Non OK
BTMC* BTMC*
Ok Ok Ok Ok
Ok
In-house
Subcontracted Identified Leads
* BTMC= Back to medicinal chemistry
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17. Hits Optimisation / Leads Identification – Case Study
Early ADMET – case study
Objective: To go up to lead identification, some biology was required
in order to select the most promising chemical families, to rank
them and to guide the medicinal chemists.
Realisation
Biological assay of the hits and analogues synthesised by chemists
Early in vitro ADMET tests discussed with the client
Cytotoxicity
Solubility
Plasmatic stability
Permeability on PAMPA
Ames Assay
Exploratory Pk
Duration: 9 months for 3 chemical families (average size of familly 15
to 20 compounds) in parallel of chemistry optimisation programme
Required resources are measured in terms of FTEs
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18. Leads optimisation
Medicinal chemists, biologists cheminformatics specialists and
preclinical development specialist work closely together to
accelerate your leads optimisation and your preclinical
development. You can pick up what you need to support your
project.
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19. Leads Optimisation - Case study
Biological Assay
Biological Assay
Screening test
Screening test
Identified Leads
Identified Leads
33to 66Famillies
to Famillies
SAR Analysis
SAR Analysis
Design and synthesis of new and patentable
Design and synthesis of new and patentable
molecules
molecules
ADMET
ADMET
Exploratory in vivo toxicity
Exploratory in vivo toxicity
Exploratory in vivo Bioavailability
Exploratory in vivo Bioavailability
Non GLP Ames assay, hERG Chanel assay
Non GLP Ames assay, hERG Chanel assay
Pre-clinical studies
Pre-clinical studies
POC in animals
POC in animals
Regulatory non clinical development
Regulatory non clinical development
Optimised leads
Optimised leads
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20. Leads optimisation – Case study
Medicinal Chemistry – SAR Analysis
Our scientists refine SARs against previously generated
data and following discussion with chemists, biologists
and computational chemists. The aim is to pick up and
optimise leads with the best chances of being active in
vivo. We also synthesise metabolites in order to
monitor their biological activity.
We design and synthesise new patentable
molecules following SAR Analysis. Our staff
members have many years of experience in the
medicinal chemistry area.
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21. Leads optimisation – case study
Exploratory in vivo ADMET
We have partnerships with acknowledged specialists in
early in vivo bioavailability and toxicity studies for
the most promising lead compounds upstream in drug
discovery process in order to confirm previous in vitro
ADMET results.
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22. Leads optimisation – case study
Preclinical Studies
Idealp-Pharma can manage its customers’ in vivo proof
of concept if needed and requested by its customers.
Non-clinical development
Idealp-Pharma can manage its customers' preclinical
development of its clients because drug discovery,
optimisation and development are all interlinked. We
help our customers to complete their requirements for
INDs and IMPDs : preliminary formulation, scale-up,
toxicology studies, CMC, safety pharmacology and
genotoxicity .
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23. Leads optimisation – case study
Leads Optimisation – case study
Objective: 1 or 2 optimized leads, ready to enter regulatory
non-clinical development
Realisation
Fully integrated services including medicinal chemistry, biology,
in vivo ADMET
- Medicinal chemistry : Analyses of SARs, design and
synthesis of new and patentable molecules with appropriate
ADMET properties, patent exemplification, synthesis
reinforcement and strategies
- Biology and ADMET : Assay of newly synthesized
compounds for their biological activity, exploratory in vivo
bioavailability,exploratory general toxicity, non GLP Ames test
and hERG channel (binding assay)
Duration: 12 months for 3 Leads
Required resources are measured in terms of FTEs
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24. Work practices
Key project management steps
Signature of a confidentiality agreement
First meeting with focused discussion between the partners
Rapid project proposal and pricing from our team
Terms agreed, followed by contract drafting
Selection of a dedicated PhD-level project manager and the project team
Scheduled project meetings/reports and/or on request: face-to-face
and/or phone meetings, encrypted e-mail, etc.
Final report and product delivery
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25. Work practices
Idealp-Pharma’s values
High-quality work which meets your needs
Meeting your deadlines
Responsiveness and flexibility : our customers can refocus their project
at any time during the collaboration
Transparency
Rigorous procedures for data management, backup and security
For each project, required resources are measured in terms of FTEs
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26. Thanks for your attention
Idealp-Pharma is your drug discovery partner
from biological target to first-in-man use
www.idealp-pharma.com
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