Download Document

Hit to lead
Pharmaceutical chemistry
Hit to lead
Chemistry in R&D
TARGET
I
D
E
A
Exploratory
research
CANDIDATE
Therapeutic
research
POC
Exploratory
development
hit/lead identification
Full
development
Synthesis
optimization
Optimization of the leads
To improve potency, selectivity, PK or reduce toxicity
D
r
u
g
Hit to lead
Chemistry in R&D
• Hit/lead identification
• Leads’ optimization
• Synthesis otpimization
• Chemoinformatics
• Combinatorial chemistry
Medicinal chemistry
Organic chemistry
Hit to lead
Research operating plan
Compounds genereted
by medicinal chemistry
Human and rat functional assay
h- and rP2Y12
h- and rP2Y12
EC50 <100 nM
Emax > 80%
selectivity over P2Y2,4,etc
hERG, hPXR
> 100
Rapid rat PK
AUC > 1000 nM.hr
Platelet aggregation test
Further characterization in other models
Rat liver slice enzyme induction
CYP450 inhibition
Hit to lead
P2Y12 antagonists SAR
From ADP to AZD6140
ADP
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
Neuropathic pain. Gold
Standards:
Gabapentin/Pregabalin/D
uloxetine
Candidate
Gold Standards’
Profile
Efficacy
• Some types of
Neuropathic pain –
(DbN, chemotherapy,
HIV)
• 30 % -50% responders
Safety
• Minimal safety issues
Indication
Tolerability
Dosing
• Dizziness, somelence
(GB), nausea, vomiting
(Dulox)
• Oral QD
• Titration ~2-4 weeks
(GB)
differentiator
• All Neuropathic Pains
• Greater responder rate (
>50%)
• Similar
• Superior
• BID acceptable with
incremental efficacy
• No titration
Candidate Profile
High
Indication
Efficacy
Medium
UNMET NEED
Tolerability
Low
Safety
Small
PERCEIVED
accettabile
non
accettabile
Dosing
Medium
ottimale
High
DIFFERENTIATION
R&D process for a new drug
TARGET
I
D
E
A
Exploratory
research
CANDIDATE
Therapeutic
research
Exploratory
development
Candidate development
POC
Full
development
D
R
U
G
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
CANDIDATE
POC
Exploratory
development
Developpability
Phase 0 or
Preclinical
development
Safety
Phase I
(A and B)
Full
development
Therapeutic efficacy
Phase II
Study in the
patient
D
R
U
G
Pre-marketing
Phase III
Study in the
patient
Registration
Phase IV
Post marketing
Surveillance
Phase 0
Preclinical development
Is the molecule suitable to be developped in a drug?
• ADME
• Preclinical Safety e Toxicology
• Chemistry development
• Formulation
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
Extravascular
Intravascular
Oral
Sublingual
Intravenous
Intra-arterial
• Directly into the blood streem
• Immediate and full absorption
Buccal
Intramuscular
Subcutaneous
Dermal
• Absorption is retarded and incomplete
It is the preferred route
when an immediate effect
is necessary
All the other cases
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
The fate of a drug
Orally
Administered
D
Drug (D)
D
Heart
Tissues
(Site of Action)
Vena
Cava
GI Tract
•Dissolution
•Acid Instability
•Digestive Enzymes
•Permeability
•Intestinal oxidation
or conjugation
•p-Glycoprotein efflux
•GI Transit time
•Bacterial metabolism
D
Portal
Vein
M
D
D
D
Bile Duct
•Re-absorption of drug
•Hydrolysis of glucuronide&
reabsorption of parent
M
•Clearance
•Distribution Cp
•Elimination
Time
M
Liver
Small
Intestine
Systemic
D Circulation
M
D
•Metabolism
•Biliary Excretion
•CYP Inhibition
•CYP Induction
•Transporters
Legend
D = Parent Drug
M = Metabolite(s)
D
Kidney
M
•Excretion of parent
•Excretion of metabolite
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
Bioavailability: (AUC)oral / (AUC)iv
8
10
Understanding Dose-Related Exposure
(single-rising dose: SRD)
Case A:
Linear (i.e dose-proportional PK)
Absorption & Clearance are constant
AUC
or
Cmax
Dose
Case B:
Saturable Elimination
AUC
or
Cmax
Dose
Case C:
Saturable Absorption
AUC
or
Cmax
Dose
The Ideal DMPK Profile
versus Lead Optimization
Clinical DMPK Profile
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:
Rationale
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