IPS1: Drug Discovery and Development Part 1

Innovator drug

the first drug created containing an active ingredient, with established efficacy, safety and quality and received approval for use

Drug Discovery Cycle

1. Compounds collection are screened against biological target (receptor, enzyme, bacteria, etc.)

2. Active compounds are identified ("Hits")

3. Hits are assessed to identify leads

4. Iterative rounds of design, synthesis, and evaluation are used to develop Structure-Activity-Relationship

5. Additional secondary assay are used to optimize compounds into clinical candidates

Stages of Drug Discover and Development Process

Hits

product of high throughput screening

Lead optimization

additional secondary assays are used to optimize compounds into clinical candidates

Product discovery

Target selection

Lead discovery

Medicinal chemistry

Drug development

In vitro studies

In vivo studies

Clinical trials

In vivo studies methods

High-throughput

Longitudinal

Non-invasive

In vivo studies processes

1. Model development

2. Target validation

3. Measure off-target effects

4. Data management

Human immunodeficiency virus (HIV)

causative agents of AIDS

AZT - Azidothymidine (Retrovir)

first reverse transcriptase approved for the management of AIDS

Highly Active Antiretroviral Therapy (HAART)

multi-drug cocktail treatment regimens for AIDS

True

True or False:

Overall cancer death rates in the United States have declined by 27% between 1991 and 2016 as a result of drug discovery and development of novel therapeutic agents.

The process of drug discovery

multidimensional and requires the coordinated effort of individuals with a wide array of expertise

Best Selling Pharmaceuticals of 2018

Adalimumab

Apixaban

Lenalidomide

Nivolumab

Pembrolizumab

Etanercept

Trastuzumab

Bevacizumab

Rituximab

Adalimumab (Humira)

for rheumatoid arthritis

Apixaban (Eliquis)

anticoagulant

Lenalidomide (Revlimid)

multiple myeloma

Nivolumab (Opdivo)

oncology

Pembrolizumab (Keytruda)

oncology

Etanercept (Enbrel)

for rheumatoid arthritis

Trastuzumab (Herceptin)

for breast cancer

Bevacizumab (Avastin)

for colon cancer

Rituximab (Rituxan, MabThera)

non-Hodgkin's lymphoma

$ 1.75 Billion

estimated cost of discovery and development of one single new drug

100,000

Estimated candidate compounds

< 0.001%

estimated success rate of drug discovery and development

Drug Discovery and Development Timeline

Drug Discovery and Development

Strategic research

Target discovery

Exploratory research

Hit generation

Lead identification

Candidate drug selection

Lead optimization

Animal models

Full development

Clinical trials

Drug discovery

concept to drug molecule

Drug Discovery

1. Target discovery

2. Target validation

3. Lead discovery

4. Lead optimization

1. Target discovery

the choice of a disease area and identification of a biological target

Approaches in Target Discovery

Data mining using bioinformatics

Genetic association

Expression profile

Pathway and phenotypic analysis

Functional screening

2. Target validation

process by which the expected molecular target - for example gene, protein or nucleic acid of a small molecule is certified

Target validation strategies

SAR of the analogs

Generation of drug-resistant mutant

Knock-down/over expression of target

Monitoring the known signaling systems downstream of the presumed target

Key steps of target validation

A. Reproducibility

B. Introduce variation to drug-target environment

3. Lead discovery

structurally related compounds with the desired biological are identified (HIT and LEAD) through biological screening of large number of compounds

Lead discovery

SAR defined

Drug ability (preliminary toxicity)

Synthetic feasibility

Select mechanistic assays

In vitro assessment of drug resistance efflux potential

Evidence of in vivo efficacy of chemical class

PK/Toxicity of chemical class known based on preliminary toxicity or in silico studies

4. Lead optimization

lead compounds are modified and studied to identify potential candidate for drug development

Lead optimization evaluation

selectivity and binding mechanisms during lead optimization, as the final step in early-stage drug discovery

Goal of lead optimization

Maintain favorable properties of the lead while enhancing the deficiencies found on the lead structure

Drug Development

5. Product characterization

6. Formulation Development

5. Product characterization

size, shape, strength, weakness, use, toxicity, and biological activity

early stages of pharmacological studies are helpful to characterize the mechanism of action of the compound

6. Formulation development

Pharmaceutical formulation is a stage of drug development during which the physicochemical properties of active pharmaceutical ingredients (APIs) are characterized to produce a bioavailable, stable, and optimal dosage form for a specific administration route

Parameters evaluated in formulation development

1. Solubility

2. Dissolution

3. Stability

4. Particle size technology

5. Formulation services and capabilities

6. Formulation of NCE

7. Optimization of existing formulas

8. Process development

9. Novel drug formulation

10. Special release formulations

11. Nanotechnology

12. Special DDS

*insert other specific info under drug discovery