Hit to lead
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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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Pharmaceutical chemistry

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Pharmaceutical chemistry

Hit to lead

Pharmaceutical chemistry


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

research

Exploratory

development

Full

development


Pharmaceutical chemistry

  • 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


P2y12 antagonists sar

From ADP to AZD6140

ADP

Hit to lead

P2Y12 antagonists SAR


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


Pharmaceutical chemistry

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


Pharmaceutical chemistry

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


Pharmaceutical chemistry

High Medium Low

UNMET NEED

Indication

Efficacy

ottimale

accettabile

Tolerability

non

accettabile

Safety

Dosing

Small Medium High

PERCEIVED DIFFERENTIATION

Candidate Profile


Pharmaceutical chemistry

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


Pharmaceutical chemistry

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)


Pharmaceutical chemistry

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


Pharmaceutical chemistry

Phase 0

Preclinical development

Is the molecule suitable to be developped in a drug?

  • ADME

  • Preclinical Safety e Toxicology

  • Chemistry development

  • Formulation


Pharmaceutical chemistry

-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.


Pharmaceutical chemistry

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


Pharmaceutical chemistry

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


Pharmaceutical chemistry

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)


Pharmaceutical chemistry

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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