Drug Discovery Module 21 PDF

MODULE 21: DRUG DISCOVERY NOW Choosing Disease Unmet Serious condition and existing therapy is inadequate medical - Serious = health is deteriorating need - Inadequate: Drugs are resistant, the effective dose has many adverse effect Economic Size of Target...

MODULE 21: DRUG DISCOVERY NOW Choosing Disease Unmet Serious condition and existing therapy is inadequate medical - Serious = health is deteriorating need - Inadequate: Drugs are resistant, the effective dose has many adverse effect Economic Size of Target - Orphan diseases have additional challenges viability Population - Definition of orphan in terms of population number is different in different countries - Large target population = large market = large return for companies Purchasing Power - Less in low- and middle-income countries - Or if disease is higher in third world countries but not in developed countries Feasability of drug - Lower risk draws more funding development - Information about the disease What makes a drug a good target - Involved in pathophysiology of disease - Primarily expressed on tissue of interest à Otherwise can cause on target adverse effects on off target tissues Known 3D structure - Druggable – target can be altered in desired manner by low molecular weight compounds - Assays available for high-throughput screening or assays can be developed Druggability - Likelihood that target can be modulated by low molecular weight compounds with ‘drug-like’ properties o So its orally active and bioactive o Has high affinity o High potency = less potential for adverse effects - Can be predicted o Use information about structure and endogenous ligand § Small drug with one target = good target § Large protein with multiple binding sites = bad target o Use information about its family § Previous successfully targeted proteins? o Not perfect - Human genome ≈20,000-22,000 protein encoding genes o Druggable genome ≈ 3,000 o Drug target ≈ 600-1500 o Disease modifying genes ≈ 3,000 Target identification and validation - Evidence that target is involved in disease pathogenesis - Evidence that modifying the target alters disease state - Target identification and validation: o requires understanding of molecular mechanisms of disease o sometimes relatively straightforward (monogenic diseases) but often not (polygenic diseases) § monogenic = C-C gene for cystic fibrosis o can use big data § some gens are upregulated/downregulated during disease  Assay development – Screening – Hits & Leads - Target Based Drug Discovery Development of assay to high- Screening Hit and lead identification throughput screening are often biochemical or cellular - large small molecular library = costly - confirm chemical hits - can assess binding and/or functional - focused library = can be aided by - physiochemical properties and selectivity activity structure based drug design or ligand (often in silico) - ideally surrogate for clinical based design = cost effective - PD = rand potency endpoint - Toxicity Target-based vs phenotype-based Target Phenotype You have identified and validated a target. You - You have a compound eliciting a desired phenotype. You identify the target develop assays and screen compound libraries to retrospectively. identify ‘hits’. - Don’t need to know the target mechanism, will figure out after - Was used most before the human genome was fully sequenced What information about a drug might be important before starting clinical trial? - Side effects - EC50 - Toxicity - Lipid solubility - Drug-drug interactions - Half-life - Efficacious dose - Vd - Bioavailability - Metabolism Preclinical development: What’s on the IND dossier - IND dossier o Submission made to FDA to allow the drug to be considered for clinical testing - Information includes o Toxicity profile o Pharmacological profile = in vitro and in vivo § Pharmacodynamic and pharmacokinetic data (ADME), information about dose, frequency, route of administration o Chemical/manufacturing info, composition/source of natural products o Formulation § Combination of drug substance with other substances, often to aid administration/compliance, stability/shelf life § Dose and administration route determined using animals before testing on humans àHelps understand toxicity o Proposed clinical plans/protocols Toxicity testing Systematic and hierarchical Acute Chronic Length of study (exposure to drug) (in vitro, ex vivo, in vivo) effect of single exposure to high effect of long-term exposure to depends on intended clinical use dose over 6-24 months Unsafe drugs - catalysts for toxicity testing - Thalidomide: indicated for morning sickness - Discovered to be teratogenic (led to malformed infants) o Was originally tested in rats which were more resistant to the drugs - Changed regulatory landscape  Mandatory testing of drugs for teratogenic potential Previously, testing was not mandatory (and not regularly performed) - So now we have to test drugs in 1 rodent and 1 non-rodent species before testing on humans Characterising pharmacological profiles - Systematic and hierarchical! o (in vitro, ex vivo, in vivo – rodents to primates) o pharmacological assays should reflect disease - Can be used to assess safety by identifying pharmacodynamic effects of a substance on physiological functions. Adverse effects may be, o Predictable § related to mechanism of action on desired target in intended tissue or unintended tissue § related to off-target effect associated with chemical class o unpredictable § unrelated to mechanism of action Clinical trials - Test the compound in humans to determine o tolerability o effectiveness o whether the compound elicits adverse effects o whether the compound elicits other beneficial effects Phase 1à in humans 2 3 4à Drug has been approved No. of Small group of healthy Larger group of healthy Large number of patients General population People volunteers (20-80) volunteers (several with the disease (several - How effective is the drug in the Enrolled Not always healthy, if hundred) or hundred to several general population? we are testing drugs Small group of diseased thousand) - Greater interpatient variability. such as chemotherapy patients - Not controlled environment. Study - Is the drug safe? - Is the drug safe? - How effective is the Larger population. Purpose - What are the - Dose - how much and drug (is it working as - Continued monitoring of safety adverse effects? how often? intended in the specific and adverse effects - Is the drug - How effective is the target population)? - Can uncover rare adverse effects tolerable? drug (is it working as - Often compared to due to larger population. - Pharmacokinetics/ intended in the standard intervention, - Drugs can be withdrawn if adverse Pharmacodynamics specific target another experimental effects are severe. population)? intervention or non- - May prompt changes in mitigation interventional standard strategies (e.g. changes in the care. drugs regulation such as labelling) Duration Several months Months to 2 years Continued monitoring of Forever adverse effects 1-3years