Rationale Drug Design
Validated biological Targetversus Drug(that optimally interacts with the target) Triggering of desired biological action
Receptor-based drug design
3D structure analysis of biological target
Pharmacophore-based drug design
Structures of known active small molecules
Main stages of drug discovery and development.
Drug Discovery, Preclinical Development Phase, Clinical Development Phase
Drug Discovery
Identification of candidate molecules on their pharmacological, biochemical and physicochemical properties.
Preclinical development
Non-human studies to determine basic pharmacokinetics, potential toxic side effects and formulation.
Clinical Development
Determination of efficacy, side effects and optimum dosage in volunteers and patients.
Describe (i) of Drug Development
(a). Chemical or biochemical synthesis of novel compound.
(b). Isolation of active ingredient from natural source
(c). Production and isolation of Biologicals
(ii) of Drug Development
Pre-clinical testing 1: effects of drug on cellular function
(iii) Drug Development
Pre-clinical testing 2: Mechanism of drug action
(iv) of Drug Development
Pre-clinical testing 3: Toxicity testing (in vivo & in vitro & ex vivo)
(v) of Drug Development
Phase 0 - human micro dosing. Pharmacokinetic profile of extremely low, non-pharmacological drug doses.
(vi) Drug Development
(vi) Phase 1 - clinical trial : on healthy subjects
Effects on body functions; drug safety
(vii) Drug Development
(vii) Phase 2 - clinical trial: on selected patients
(viii) Drug Development
(viii) Phase 3 - clinical trial: on large groups of patients
- Comparision to other therapies
(ix) Drug Development
Approval: Licensing by National Regulatory Agency
Drug Development (x)
Phase 4-clinical trial: Long-term benefit-risk evaluation Determination of THERAPEUTIC VALUE of novel drug or delivery system
Post-marketing of novel substance (post-licensing studies) - pharmacovigilance
What is target selection and what is of based on?
- Target selction: usually a defined protein species
- Often based on biomedical knowledge on, disease mechanisms, biochemical pathways and cellular signaling.
Drug Discovery - identification of lead compound
- Large compound libraries
- High-throughput HTP screening of 1000s of compounds
- Determination of half-maximal effective concentration Ec50 of novel compound after a specified exposure time.
What animals are used in the detmination of median effective dose ED50?
Mice, rats, rabbits
Assement of toxicity
- single dose of increasing strength (2 species, both sexes, different ages)
- different routes of administration (1-7 days)
- Determination of median lethal dose LD50
Assessement of subacute toxicity
only done once lethal dose has been determined.
- several routes of administration (2-12 weeks0
- several species; several dosages.
Assessment of chronic toxicity
- chronic 3-12 months testing in several species
- evaluation of potential carcinogenic effects
- special teratogenic tests on pregnant rats
Health interventions that require differing degrees of testing are?
- Pharmaceutical agents
- Novel drug derivatives
- New drug combinations
- Diagnostics
- Medical devices
- Therapy protocols
