Lecture 12 Flashcards
ADMET
1
Q
Drug Development
A
- Ancient history - raw herbals, often still popular
- History - isolate pure(ish) natural product actives
- Recent History - tinker on peripheries of isolated natural product actives, EX: Morphine => Heroin via acetylation
2
Q
Screening Libraries
A
- 1 or the 2 ways to screen for effective drug compounds
- Compound library of hundred to millions of individual compounds of usually known structures
- Key asset to pharmacology
3
Q
Why not use crystal structure and rationally design?
A
- Most receptors = membrane proteins
- Enormously difficult to crystallize
4
Q
In Vitro Screens
A
- Libraries are useful towards these tests
- Larger libraries get more hits, so HTS = more common
- Robotic, multiwell plates, optical readouts
- Libraries and in vitro screens go on to feed the next step: Developing SAR
5
Q
Develop SAR
A
- Want to find 10-100 “drug-like” potentials
- Resynthesize diverse mini-library based on main compound’s skeleton - 100-1000s
- Often use bioisoteric replacement to swap out groups that behave and interact with targets similarly (EX: replacing a phenol with a pyridyl or thiophenyl)
- Also guided by periodic table, move 1 row up or down
- Move columns less since it can cause issues with valence and acid/base reactions
- *Often switch H => F to prevent P450 mediated oxidation)
6
Q
Crystal Structures
A
Save lots of time by guiding development of the ligands
7
Q
Fragments
A
-Instead of trying to match all receptor-drug interactions at the same time you build the compound piece by piece to fit the model and amalgamate into potentially synthesizable molecule
8
Q
Animal Models
A
- Sometimes use animal models at this point to test the molecule that was development
- Run 5-10 top choices through in-vivo screen
- See how this affects SAR ranking based on drug activity
9
Q
Poor ADMET drives…
A
60% of drug failure. All the development takes time and money, sometimes up to 10-20 years and $500-1000 million.
10
Q
Why Drugs Fail (4)
A
- Poor biopharmaceutical properties (bad ADME), 39%
- Lack of efficacy, 29%
- Toxicity, 21%
- Market reasons, 6%
* *Adverse ADMET leads to 60% of wastage**
11
Q
ADMET
A
- Easier than Bioactivity to predict
- Determined largely by physicochemical properties
- Absorption/Distribution - largely determined by solubility and permeability
- Metabolic enzymes have low stringency due to evolution pressure to deal with a large pool of xenobiotics
- Toxicity - large component of chemical reactivity (simple rules work)
- ADMET towards receptors is much more difficult due to their high stringency and dimensionality in chemical space (simple rules don’t work)
12
Q
A
A
- Absorption
- In absence of transporters, this is driven by Lipinski’s rule of 5
13
Q
H Donor
A
H attached to heteroatom (O, N, S) that is partially negative in charge.
14
Q
H Acceptor
A
A heteroatom (O, N, S)
15
Q
D
A
- Distribution
- Methods of transport depend on ligand polarity
- Can deliver compound by diffusion or receptor
16
Q
Methods of Transport (3)
A
- Free in solution (polar)
- Bound to proteins like albumin (intermediate polar, common)
- Bound to lipoprotein complexes (very hydrophobic)
17
Q
High Protein Binding
A
- BAD due to efficacy and displacement potentials, EX: 99% of a drug is bound to protein so only 1% is available for action
- Other molecules that displace ligands can cause toxicity (more molecules free to cause toxicity)
- *NOT A HUGE CONCERN IN DEVELOPMENT, RULE OF 5 TAKES CARE OF MOST OUTLIERS**
18
Q
M
A
- Metabolism
- Small, polar molecules are excreted by the kidneys
- Many drugs that are too non-polar go through oxidation to become a conjugate that can be excreted via the liver (EX: aromatic and aliphatic compounds)
- Need to find the polar balance to promote excretion
- Prefer slow, predictable metabolisms to cause inactivation or excretion, avoid excretion via problem enzymes
19
Q
Problem Enzymes
A
- P450 3A4 - tons of inhibitors/inducers making drug-drug interactions common
- Acetylation rates are variable and can cause varying levels of metabolism in drugs like isoniazid which can lead to hepatotoxicity
20
Q
Prodrugs
A
- Can allow for absorption of Ro5 breaking compounds
- Mask polar functionalities with esters and amides
- Can be unmasked via P450 oxidationw
21
Q
E
A
- Elimination
- Usually not a problem for development
- Sometimes specialized pathways are needed (EX: antiobiotics being active and renally excreted to treat UTIs)
- Done by radiolabelling parent drug to see where it goes, most commonly excreted in urine or bile (can also be done in breath, sweat, and tears)
22
Q
T
A
- Toxicity
- All drugs are toxic depending on the dose
- Many drugs are withdrawn or Black-boxed due to reactive metabolites
- Try to avoid ligands with chemical strucure that is predisposed to reactive intermediates (EX: aromatic nitros, Michael Addition sites, molecules that are damaging and form HAPTENS)
- Try to screen drugs earlier now to lose leads and take less massive costs compared to toxic blockbusters
23
Q
Toxicity Types (5)
A
- On-target Tox. - Mechanism based, same receptor and wrong tissue (Ex: Statins)
- Off-target Tox. - EX: Terfenadine and hERG channel effects
- Biotransformation to reactive intermediates - acetaminophen
- Hypersensitivites & Immune Response - penicillin
- Idiosyncratic Tox. - rare events that don’t fit the other categories
1/2 are sometimes spotted in animal or early trials, but sometimes only when released to larger populations which lead to Black Box or withdrawal
4/5 - dose dependence often isn’t clear
