lead optimisation

lead optimisation

• refine the lead series to improve their potential as safe and effective therapeutic drugs

what are the aims of lead optimisation

• potency against target

• efficacy against target

• selectivity for target

• duration of action

• pharmacokinetics

• toxicity profile

• patent position

• scale up for manufacturing

• formulation and route of administration

in vivo lead optimisation goals

• solubility

• high potency against molecular target

• good efficacy

• activity against clinically relevant biomarkers

• good free drug exposure levels

• acceptable cost of goods

• administration is easy eg oral

what are the different target related and off target toxicities that need to be assessed for lead optimisation

• mechanism related

• dose limiting

• no QT liability

• no adverse drug drug interactions

• no genotoxicity

• large therapeutic window

time scale of development of candidate drug

• hit identification - 9-10 months

• lead generation - 6-9 months

• lead optimisation - ideally 2,3 years to give 1 or 2 compounds

aim of medicinal chemistry

• simplification of the molecule

• easier to scale up and manufacture

• better pharmacokinetics

• less likely to have non specific interactions

Examples of simplification designs in medicinal chemistry?

• SAR based design

• structure based design

• pharmacophore based design

Examples of modifications towards enhancing metabolic stability

• reduction in size but maintain lipophilicity

• deactivate aromatic rings

• stereoisomerisation

• constrain molecule so less likely to undergo metabolism

• avoid phenolic groups

Example of lead optimisation from core structure where the structure was not simplified

• imatinib - tyrosine kinase inhibitor

• change of ring structure by adding certain groups

• enhancement of cellular activity, elimination of PKC

Steps from lead identification to lead optimisation, summary of a typical pharmacological screening cascade

• activity in primary screen - hts binding assay

• potency against target in cell based assay

• selectivity of action

• functional potency in cell based screens

• in vivo potency

• duration of action in vivo

• activity in disease model

Output and Information from lead identification to lead optimisation

• high throughput to low throughput

• low information to high information

Key elements of potency against target in cell based assays

1.Quantification of compound effect on target to measure potency

2. Selective readout for target

3. Robust and reliable assay format

4. Reproducible data

5. Quick and simple to run

6. scale up or down to cope with large or small numbers of compounds

Key elements of in vitro functional cell based assays

1.Quantification of compound effect on cellular phenotype/behaviour

2. Robust and reliable assay format

3. Reproducible data

4. Can scale up to cope with large of compounds

Considerations for in vivo biological assays

• relationship between inhibition of target and consequences

• target biology understanding

• confidence in reagents and assay

• interpretation of data

• is in vitro reflective of in vivo

in vitro assays to test for chemical modifications in lead optimisation

• pharmacological screening

• potency against target in cell based assays

• functional cell based assays

in vivo assays to test for chemical modifications in lead optimisation

• pharmacodynamic assays

• disease modelling

Why do we want potent compounds?

• dose required is likely to be lower

• less likely it is to have general toxicity

  • can still carry target specific or mechanistic

• helps lower production costs

Pharmacodynamic assays

• mathematical relationship measuring compound effect on target, pathways downstream and biological function

• seen in vivo assays

Disease modelling

• test the hypothesis - desired effect in clinic

• measure change in disease model

• measure change in a surrogate

  • evidence of hitting a molecular target

Considerations of in vivo biological assays

• can target be measured from tissue samples

• does the disease model accurately reflect the human disease

• correlation between mouse and human

• does the measurement of target inhibition in the tissue mimic target inhibition in the disease

translational biomarkers in pharmacodynamic assays

• confirmation a drug hits a target

• evidence from animal models and human clinical trials

• eg blood pressure, glucose levels allow direct comparison between species

applications of biomarkers in pharmacodynamic assays for drug development

• dose selection

• proof of biological effect

• patient selection - who will have higher probability of response

Explain the general principles of how lead optimisation brings effective and safe drugs through to the preclinical stage. (5 marks)

• medicinal chemistry - simplification

  • structure- activity relationships

  • pharmacophore refinement

• improving potency and selectivity

  • measured in potency against target cell based assays

  • higher potency, lower doses, fewer side effects

• modification to prevent rapid metabolism

  • avoid phenolic groups, stereoisomerisation

What is the definition of a biomarker? (2 marks)

• defined characteristic that is objectively measured and evaluated as an indicator of biological processes, pathogenic processes or pharmacologic response

• eg blood pressure, protein level