Idealp Pharma Hits & Leads Optimisation Case Study 1

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

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Idealp Pharma Hits & Leads Optimisation Case Study 1

  1. 1. Idealp-Pharma Hits optimisation / Leads identification / Leads optimisation Case study
  2. 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. -2-
  3. 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 -3-
  4. 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 -4-
  5. 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. -5-
  6. 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 -6-
  7. 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. -7-
  8. 8. Hits Optimisation / Leads Identification – Case Study Cheminformatics – SLF-Libmaker® -8-
  9. 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. 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 - 10 -
  11. 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. - 11 -
  12. 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 - 12 -
  13. 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 - 13 -
  14. 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 - 14 -
  15. 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. - 15 -
  16. 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 - 16 -
  17. 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 - 17 -
  18. 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. - 18 -
  19. 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 - 19 -
  20. 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. - 20 -
  21. 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. - 21 -
  22. 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 . - 22 -
  23. 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 - 23 -
  24. 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 - 24 -
  25. 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 - 25 -
  26. 26. Thanks for your attention Idealp-Pharma is your drug discovery partner from biological target to first-in-man use www.idealp-pharma.com - 26 -

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