All compounds are unique and this list should only regarded as a guideline.
- Activity in two in vivo preclinical efficacy models, including plasma level efficacy profile. In most cases this will need to be < 10 nM in vitro and < 10 mg/kg p.o. in vivo. Remember an in vivo efficacy model in which you block the effect of an applied agonist can obviously be manipulated by changing the dose of agonist.
- A list of all completed and ongoing preclinical ADME and human biopharmaceutical studies. A one page summary is very useful.
- Ensure the assay method that was used in quantitation of the compound in plasma and/or urine samples from laboratory animals is valid for humans. Is the method validated as per the FDA criteria?
- Complete pharmacokinetic parameters following oral and intravenous administration in two species, ideally species to be used in proposed safety studies.
- Ensure dosing/formulation/route of administration will allow adequate coverage in proposed safety studies.
- For intravenous administration check for haemolysis using the proposed vehicle.
- Check the distribution of the compound in laboratory animals, including brain and binding to melanin containing tissues. Is there a long-lived component in plasma and tissues? This will probably require labelled compound.
- Identify the routes of excretion and mass balance in laboratory animals following oral and intravenous administration of radiolabeled compound.
- Identify the pathways of metabolism of the compound in laboratory animals. Does metabolism lead to the formation of pharmacologically active metabolites?
- Define the metabolism of the compound in vitro using liver sub-cellular fractions from laboratory animals and human, including metabolite characterization and kinetics of metabolite formation.
- Identify the enzymes responsible for the metabolism of the compound in human, are they different in toxicological species?
- Complete inhibition profile of the compound against CYP enzymes and Pgp. Is the compound a pre-incubation time-dependent inhibitor of CYP enzymes? Ideally no activity below 10 uM
- The propensity of the compound to generate reactive intermediates. What is the degree of irreversible binding to liver microsomal proteins in vitro and plasma/liver proteins in vivo?
- Does the compound cause CYP induction? Ideally no activity below 10 uM
- Check the plasma protein binding and blood/plasma ratios of the compound in laboratory animals.
- Model plasma profile versus efficacy and off-target activity/toxicity. Remember for some therapeutic targets you may need to maintain 100% occupancy.
- AMES Test (up to maximum solubility), HERG Binding, if any binding seen below 10 uM, look for QT prolongation in vivo .
- Selectivity screen, PanLabs or similar.
- Define the pharmaceutical properties of the molecule. Melting point (if possible Differential Scanning Calorimetry or Thermal Analysis), stability, solubility, purity, pKa etc. for both free base and salt if appropriate. Any evidence for polymorphs? Define formulations.
- Stability at high temperature (30-60oC) and high humidity.
- Ensure freedom to operate, including all intermediates in synthetic route.
- Ensure a chemically tractable synthesis capable of producing enough material at least for safety studies, preferably a potential manufacturing route.
- Competitive position, both for ligands for the same molecular target but also compounds addressing the same therapeutic target.
Last Update 30 Nov 2009