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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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Presentation Transcript
slide1

Hit to lead

Pharmaceutical chemistry

slide2

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

slide3

Chemoinformatics

  • Combinatorial chemistry
  • Hit/lead identification
  • Leads’ optimization
  • Synthesis otpimization

Medicinal chemistry

Organic chemistry

Hit to lead

Chemistry in R&D

research operating plan

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
drug discovery process

Drug Discovery Process

Massimiliano Beltramo, PhD

the patent
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
slide8

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
slide9

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

slide10

High Medium Low

UNMET NEED

Indication

Efficacy

ottimale

accettabile

Tolerability

non

accettabile

Safety

Dosing

Small Medium High

PERCEIVED DIFFERENTIATION

Candidate Profile

slide11

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

slide12

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)
slide13

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

slide14

Phase 0

Preclinical development

Is the molecule suitable to be developped in a drug?

  • ADME
  • Preclinical Safety e Toxicology
  • Chemistry development
  • Formulation
slide15

-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.

slide16

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

bioavailability
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
slide18

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

bioavailability1
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

slide20

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)

slide21

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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