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Pharmaceutical chemistry

Hit to lead. Pharmaceutical chemistry. Synthesis optimization. hit/lead identification. Optimization of the leads To improve potency, selectivity, PK or reduce toxicity. Hit to lead. Chemistry in R&D. CANDIDATE. TARGET. POC. I D E A. Drug. Exploratory research. Therapeutic

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Pharmaceutical chemistry

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  1. Hit to lead Pharmaceutical chemistry

  2. Synthesis optimization hit/lead identification Optimization of the leads To improve potency, selectivity, PK or reduce toxicity Hit to lead Chemistry in R&D CANDIDATE TARGET POC I D E A Drug Exploratory research Therapeutic research Exploratory development Full development

  3. Chemoinformatics • Combinatorial chemistry • Hit/lead identification • Leads’ optimization • Synthesis otpimization Medicinal chemistry Organic chemistry Hit to lead Chemistry in R&D

  4. Hit to lead Compounds genereted by medicinal chemistry Human and rat functional assay hERG, hPXR h- and rP2Y12 EC50 <100 nM h- and rP2Y12 Emax > 80% selectivity over P2Y2,4,etc > 100 Rat liver slice enzyme induction CYP450 inhibition Rapid rat PK AUC > 1000 nM.hr Platelet aggregation test Further characterization in other models Research operating plan

  5. From ADP to AZD6140 ADP Hit to lead P2Y12 antagonists SAR

  6. Drug Discovery Process Massimiliano Beltramo, PhD

  7. The patent • To assure the intellectual property to the inventor. • To forbid to competitors the production, use and commercialization of the invention for 20 years. What could be claimed ? New molecules Pharmaceutical formulation Synthesis processes and industrial processes Therapeutic indication Diagnostics’ methods Biological tools (gene, transfected cell lines, assays, etc) When to patent a molecule? • In lead optimisation. This normally allow 10 years of exclusivity on the market

  8. What are the characteristics of a candidate? • Biological properties • Pharmacological profile • (potency, selectivity, efficacy in vivo) • Pharmacokinetic profile • (Biodisponibility, long lasting effect) • Preliminary toxicological profile • (tolerability, hERG, mechanism based toxicity, acute therapeutic window) • Chemo-physical properties • Scalability • Pharmaceutical formulation • Commercial potential • Unmet medical need • Differentiation

  9. Gold Standards’ Profile Candidate differentiator Indication • Some types of Neuropathic pain – (DbN, chemotherapy, HIV) • All Neuropathic Pains Efficacy • 30 % -50% responders • Greater responder rate ( >50%) Safety • Minimal safety issues • Similar Tolerability • Dizziness, somelence (GB), nausea, vomiting (Dulox) • Superior Dosing • Oral QD • Titration ~2-4 weeks (GB) • BID acceptable with incremental efficacy • No titration Neuropathic pain. Gold Standards: Gabapentin/Pregabalin/Duloxetine

  10. High Medium Low UNMET NEED Indication Efficacy ottimale accettabile Tolerability non accettabile Safety Dosing Small Medium High PERCEIVED DIFFERENTIATION Candidate Profile

  11. R&D process for a new drug CANDIDATE TARGET POC I D E A DRUG Exploratory research Therapeutic research Exploratory development Full development Candidate development

  12. Candidate development objectives • To complete the study on the candidate and to establish • Safety in human • Suitability for industrial development (exploratory development) • To establish the efficacy profile in human and to define the commercial value of the new drug (full development)

  13. Developpability Safety Therapeutic efficacy Pre-marketing Phase 0 or Preclinical development Registration Phase II Study in the patient Phase III Study in the patient Phase I (A and B) Phase IV Post marketing Surveillance R&D process for a new drug CANDIDATE POC DRUG Exploratory development Full development

  14. Phase 0 Preclinical development Is the molecule suitable to be developped in a drug? • ADME • Preclinical Safety e Toxicology • Chemistry development • Formulation

  15. -Absorption -Distribution -Metabolism -Excretion Elimination ADME Describes the disposition of a pharmaceutical compound within an organism. Drug exposure to the tissues influence the performance and pharmacological activity of the compound.

  16. Extravascular Intravascular Oral Sublingual Buccal Intramuscular Subcutaneous Dermal Intravenous Intra-arterial • Directly into the blood streem • Immediate and full absorption • Absorption is retarded and incomplete It is the preferred route when an immediate effect is necessary All the other cases Administration route

  17. Bioavailability • Fraction of administered dose that reaches the systemic circulation in the unchanged form and the target tissue • After intravenous administration, the drug is completely bioavailable (F=1) • For oral administration, incomplete bioavailability may be due to: • Transporter Effects • Incomplete absorption or loss in the feces • First pass metabolism in the gut lumen and/or liver • Major determinant for the differences in dose between the intravascular and extravascular routes

  18. Orally Administered Drug (D) D Heart D Tissues (Site of Action) Systemic Circulation Vena Cava GI Tract D M • Dissolution • Acid Instability • Digestive Enzymes • Permeability • Intestinal oxidation • or conjugation • p-Glycoprotein efflux • GI Transit time • Bacterial metabolism Cp D • Clearance • Distribution • Elimination D M M Portal Vein D Time D M Liver D Kidney • Metabolism • Biliary Excretion • CYP Inhibition • CYP Induction • Transporters Bile Duct D M Small Intestine M Legend • Excretion of parent • Excretion of metabolite • Re-absorption of drug • Hydrolysis of glucuronide& • reabsorption of parent D = Parent Drug M = Metabolite(s) The fate of a drug

  19. Bioavailability Bioavailability using different route is calculated using equal doses Plasma concentration 70 60 i.v. route 50 40 oral route 30 20 Time (hours) 10 0 0 2 4 6 8 10 Bioavailability:(AUC)oral / (AUC)iv

  20. Case A: Linear (i.e dose-proportional PK) Absorption & Clearance are constant AUC or Cmax AUC or Cmax AUC or Cmax Case B: Saturable Elimination Dose Dose Dose Case C: Saturable Absorption Understanding Dose-Related Exposure (single-rising dose: SRD)

  21. Clinical DMPK Profile Rationale High oral bioavailability: Half-life between 12 and 24 hr: Multiple elimination pathways: No reactive metabolites: No human-specific metabolites: No inhibition of CYP450 enzymes: No induction of CYP enzymes: Low inter-subject variability/ cost of goods QD dosing/ acceptable accumulation Drug-drug interactions (DDI) less likely Avoid safety issues/ idiosyncratic AEs Simplifies safety program & risk assessment Drug unlikely to cause DDIs Avoid autoinduction or DDIs Drug Safety DMPK Profile Good PK with developable form: Acceptable exposure multiples: Stable and predictable exposure: Clean in AMES test: Crystalline form - reduced bioavailability? Human risk assessment Reliably target appropriate exposure Avoid mutagens The Ideal DMPK Profile versus Lead Optimization

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