Pharmaceutical chemistry Hit to lead

Chemistry in R&D Exploratory development Full development IDEAIDEA DrugDrug CANDIDATE POCTARGET Therapeutic research Exploratory research Synthesis optimization hit/lead identification Optimization of the leads To improve potency, selectivity, PK or reduce toxicity Hit to lead

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

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

P2Y12 antagonists SAR Hit to lead ADP From ADP to AZD6140

Drug Discovery Process Massimiliano Beltramo, PhD

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

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

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

Candidate Profile Small Medium High PERCEIVED DIFFERENTIATION High Medium Low UNMET NEED IndicationEfficacy SafetyDosing Tolerability ottimale accettabile non accettabile

R&D process for a new drug Exploratory development Full development IDEAIDEA DRUGDRUG CANDIDATE POCTARGET Therapeutic research Exploratory research Candidate development

Candidate development objectives 1.To complete the study on the candidate and to establish Safety in human Suitability for industrial development (exploratory development) 2.To establish the efficacy profile in human and to define the commercial value of the new drug (full development)

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

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

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

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

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

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

Plasma concentration Time (hours) i.v. route oral route Bioavailability: (AUC) oral / (AUC) iv Bioavailability using different route is calculated using equal doses Bioavailability

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

The Ideal DMPK Profile versus Lead Optimization 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 Rationale Clinical DMPK Profile 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