Lecture 12

Question 1

Drug Development

Answer 1

• 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

Question 2

Screening Libraries

Answer 2

• 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

Question 3

Why not use crystal structure and rationally design?

Answer 3

• Most receptors = membrane proteins

- Enormously difficult to crystallize

Question 4

In Vitro Screens

Answer 4

• 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

Question 5

Develop SAR

Answer 5

• 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)

Question 6

Crystal Structures

Answer 6

Save lots of time by guiding development of the ligands

Question 7

Fragments

Answer 7

-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

Question 8

Animal Models

Answer 8

• 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

Question 9

Poor ADMET drives…

Answer 9

60% of drug failure. All the development takes time and money, sometimes up to 10-20 years and $500-1000 million.

Question 10

Why Drugs Fail (4)

Answer 10

1. Poor biopharmaceutical properties (bad ADME), 39%
2. Lack of efficacy, 29%
3. Toxicity, 21%
4. Market reasons, 6%
   * *Adverse ADMET leads to 60% of wastage**

Question 11

ADMET

Answer 11

• 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)

Question 12

A

Answer 12

• Absorption

- In absence of transporters, this is driven by Lipinski’s rule of 5

Question 13

H Donor

Answer 13

H attached to heteroatom (O, N, S) that is partially negative in charge.

Question 14

H Acceptor

Answer 14

A heteroatom (O, N, S)

Question 15

D

Answer 15

• Distribution
• Methods of transport depend on ligand polarity
• Can deliver compound by diffusion or receptor

Question 16

Methods of Transport (3)

Answer 16

1. Free in solution (polar)
2. Bound to proteins like albumin (intermediate polar, common)
3. Bound to lipoprotein complexes (very hydrophobic)

Question 17

High Protein Binding

Answer 17

• 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**

Question 18

M

Answer 18

• 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

Question 19

Problem Enzymes

Answer 19

• 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

Question 20

Prodrugs

Answer 20

• Can allow for absorption of Ro5 breaking compounds
• Mask polar functionalities with esters and amides
• Can be unmasked via P450 oxidationw

Question 21

E

Answer 21

• 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)

Question 22

T

Answer 22

• 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

Question 23

Toxicity Types (5)

Answer 23

1. On-target Tox. - Mechanism based, same receptor and wrong tissue (Ex: Statins)
2. Off-target Tox. - EX: Terfenadine and hERG channel effects
3. Biotransformation to reactive intermediates - acetaminophen
4. Hypersensitivites & Immune Response - penicillin
5. 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