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TPN, syringe drivers, Lab Results > Bench to bedside > Flashcards

Bench to bedside Flashcards

1
Q

Order of drug discovery process

A 
Discovery - target validation
hit identification
lead identification
lead optimisation
nomination phase
clinical trials - phases I-IV
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2
Q

What characteristics do we need our drug to have?

A 
good bioavailability
good absorption
slow metabolism - allow for absorption
no toxic metabolites
bodily distribution to facilitate access to the target
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3
Q

Achieving a pharmacodynamic output at a molecular level?

A

enzyme inhibition
receptor antagonism/agonism
Introduce groups which drive up affinity for the target protein to improve potency (lower dose can be given)
Introduce groups which achieve selectivity (reducing toxicity)
H-bonding drives interactions with key amino acids in the target protein
Lipophilic can provide interactions with drug target

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4
Q

Achieving the correct pharmacokinetic profile to enable access to the target for a sustained time period?

A

ADME
Where the drug goes (i.e. protein bound drug cannot exert effect)
how long it stays in the body (half life)
How it is metabolised

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5
Q

Ranges of bonds, short, mid, long

and groups typically involved

A
  1. vdW - Short range - aromatic and non-polar aliphatic side groups
  2. H-bond - Mid range - polar, uncharged side groups
    electron- deficient H.
    Electronegative atoms with lone pairs O, F, N
  3. Ionic - long range- NH3 +ve with negative (e.g. O)
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6
Q

Role of halogen in SPR profiles

A

block oxidation but lipophilic so influence water solubility therefore absorption

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7
Q

Role of hydrophilic groups

A

promote phase II metabolism and renal excretion

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8
Q

How are hits against the target identified?

A

High throughput assay. Use compound library to identify any “hits”
Target enzyme + substrate = quantifiable signal readout

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9
Q

How is inhibitory activity carried out (simple version)?

A

Target enzyme + small molecule inhibitor compared with quantified readouts

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10
Q

Optimising for potency - ABSORPTION

A

Physical properties and formulation (log D, log P)
solubility
permeability (Caco2)

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11
Q

Optimising for potency - DISTRIBUTION

A 
Vd
Bioavailability
Target selectivity
Receptor drug interactions
Protein binding
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12
Q

Optimising for potency - METABOLISM

A

Modifications - Phase I and Phase II

Renal and hepatic clearance

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13
Q

Optimising for potency - EXCRETION and TOXICITY

A

Toxicology assays - AMES - mutagenicity
HERG - screens for cardiotoxicity/arrhythmias
in vivo safe dosing, toxic dose
IC 50

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14
Q

EC50 and IC50 definitions

A

EC50 Half maximal response drug concentration

IC50 concentration of inhibitor where response is reduced by half

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15
Q

What does DMPK stand for?

A

Drug Metabolism and Pharmacokinetics

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16
Q

What is IHC?

A

Immunohistochemistry (IHC) is an important application of monoclonal antibodies to determine the tissue distribution of an antigen of interest in health and disease

17
Q

what occurs in phase 2a trials

A

dose finding and PK in 10s of patients

18
Q

2b trials?

A

confirm efficacy with confidence 10-100 patients

19
Q

binding roles:

  1. Amine
  2. Amides
  3. Carboxylic acids
  4. Esters
  5. Aromatic ring
A
  1. amine HBD/HBA if lone pair available (N)
  2. amide - HB
  3. Carboxylic acid - HB - good ligand for Zn, Ionic bonding
  4. Esters - used to mask polar groups
  5. Aromatic ring - vdWs. Phenol - HB
20
Q

Quick summary of enalapril optimisation

A
  1. Thiol improves potency (but S/Es) so replaced aromatic (S1)
  2. COOH essential for oral administration (salt forming group) - RCOOH + NaOH = RCOONa + H20
  3. Aliphatic S2 occupancy
  4. COOH binds ERG (Zn)
  5. Carboxylic acid too polar (masks as ethyl ester in prodrug)
21
Q

Summary of farnesyl transferase inhibitors

A
  1. Zn bound in FT active site increases nucleophilicity of the Cys thiol group
  2. Thiol co-ordinates Zn and has good affinity for FT site
  3. Aromatic - higher affinity
  4. Free carboxyl - affinity for binding
22
Q

in vivo test for CYP

A

liver hepatocytes + compound = metabolites and any interactions

23
Q

Planar aromatic structures in topoisomerase I inhibitors

and other drug development

A

promote stacking in solude state preventing dissolution
(inert = no salt forming groups => hydrolyse
Tertiary aliphatic amine allows formulation as a salt

24
Q

in vitro testing

  1. pharmacology
  2. PK
  3. Safety (IHC)
A
  1. affinity/potency target test, MOA, effect in complex assay system
  2. PK - Clearance, PAMPA, Caco-2 (permeability), Ussing chamber, Solubility (max absorbed dose), Plasma protein binding
  3. Safety - selectivity - affinity/potency
    specificity - cell lysis
    front-loaded HERG (cardiotoxicity)
    AMES - (carcinogenicity)
25
Q

in vivo testing

  1. pharmacology
  2. PK
  3. Safety
A
  1. Guinea pig model efficacy
  2. Clearance
    Half life
    F
    Vd
  3. Safety - absorbed from efficacy studies

TPN, syringe drivers, Lab Results (13 decks)

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