Lecture 3

Question 1

Medicinal Chemistry

Answer 1

Studies how chemical structure influences biological activities. An interdisciplinary science at the intersection of organic chemistry, biochemistry, structural biology, computational chemistry, molecular biology, and physical chemistry.

Question 2

Physicochemical Properties

Answer 2

Properties derives from how functional groups influences its acid-base properties, water solubility, partition coefficient, stereochemistry, and ability to interact with biological systems/targets, such as enzyme active sites and receptor sites.

Question 3

Biopharmaceutical Properties

Answer 3

Properties derrived from how physicochemical determine biological action of pharmaceuticals. Examples include solubility, partition coefficient, and degree of ionization, which are in turn determined by chemical structure and stereochemistry of the drug.

Question 4

Routes of Administration

Answer 4

• Choice of administration route in a given situation depends on drug and patient related factors
• Can be local or systemic
• In systemic applications, the drug is absorbed by the blood and taken all over the body

Examples of routes of administration: oral, SL, rectal, epithelial, inhalation, parenteral

Question 5

Passive Diffusion Steps

Answer 5

1. Drug in formulation
2. Drug goes through dissolution
3. Drug in solution
4. Drug is absorbed across a barrier (ex: cell membrane)
5. Drug in blood

Most drugs are absorbed via this route

Question 6

How do physicochemical properties connect to med chem?

Answer 6

• Drug must overcome many hurdles to reach its target
• Different routes have different hurdles
• Many complication biological processes can be modeled using simply physical chemistry models or processes (can increase optimization)

Question 7

3 Drug Permeation Methods

Answer 7

1. Passive Diffusion
2. Carrier-Mediated/Active Transport
3. Convective Absorption

Question 8

Passive Diffusion

Answer 8

• Most drugs diffuse via this route
• Net movement is from high concentration to low (with concentration gradient)
• Energy not required
• Related to lipid solubility (partition coefficient)
• Hydrophobic molecules can “partition” into membranes which can be measured to find coefficient P

Question 9

Partition Coefficient

Answer 9

P = Co/Cw
Co = drug concentration in oil phase (octanol)
Cw = drug concentration in water

-As P increases, the lipid solubility increases (easier to cross membrane and be absorbed)

Since range of values can vary so widely, often use log(P)

Question 10

Why Octanol?

Answer 10

• Contains 8 carbons and one hydroxyl group
• May closest mimic the bell membrane
• Gives the best correlation to actual in vivo values

Question 11

Lipid Solubility

Answer 11

• Function of combination of effects for all functional groups
• General rule: as the number of carbons and hydrogens increases, the log(P) increases (longer the hydrocarbon chain, the more lipophilic the molecule)

Question 12

Increase in log(P) correlates to…. (8)

Answer 12

1. Increased absorbed percentage of unionized drug
2. Increased clotting ability
3. Increased receptor affinity (binding)
4. Decreased aqueous solubility
5. Increased binding to P450 enzymes
6. Increased absorption through membranes
7. Increased binding to blood and tissue (less drug available)
8. Increased binding to hERG heart ion channel (increased cardiovascular toxicity)

NOT ALL OF THESE ARE DESIRABLE, MUST OPTIMIZE log(P)

Question 13

Methods to Alter Lipophilicity (5)

Answer 13

1. Replacing hydrogen with a halogen increases lipophilicity
2. Replacing hydrogen with hydroxyl decreases lipophilicity
3. Removing quinoline N to give carbocyclic ring greatily increases lipophilicity (only slightly offset by the inclusion of an ether)
4. Addition of an oxygen into ring next to nitrogen increases lipophilicity
5. Replacement of quinoline with aromatic ring increases lipophilicity (further enhanced by addition of trifluoromethyl group)

Question 14

Distribution Coefficient

Answer 14

• If compound can ionize, the partitioning of compound between water and octanol will be pH dependent
• Ionized portions will stay in aqueous solution, neutral portions will pass membrane (an octanol)

Question 15

Distribution Coefficient Equations

Answer 15

Acid: D = [HA]octanol/([HA}aq + [A-]aq)

Base: D = [B]octanol/([BH+]aq + [B]aq)

-Effective lipophilicity of ocmpound at given pH is a function of both lipophilicity of unionized compound and the degree of ionization

Question 16

log(P) v.s. log(D)

Answer 16

• log(P) measures lipophilicity of NEUTRAL compounds, only a good reference points for overall trends. Must use caution when using ionizable compounds
• log(D) measures lipophilicity of ionizable compounds since it accounts for pH
• log(D) at pH = 7.4 is the most relevant descriptor since it describes the distribution at physiologic pH

log(D) = log(P) - log[1-10^(pH-pKa)]

Question 17

Water Solubility

Answer 17

• Needed since drug needs to be in solution to be absorbed
• Greatly affects route of administration available for drug as well as its overall metabolism through the body
• Drugs needs to have a balance between hydrophilic and lipophilic so it can be carried through the body in the blood AND be able to cross cell membranes

Question 18

Drug Characteristics Affecting Water Solubility (2)

Answer 18

1. Functional groups that increase polarity (H-bonds)

2. Ionization: weak acids and weak bases

Question 19

Polarity

Answer 19

• Structural groups effect on solubility
• Only C-H and C-C bonds are relatively nonpolar
• Heteroatoms of N or O which create partial negative charges that can form H-bond with water

Can also chemically modify a drug to increase its lipophilicity so that the modified structure has similar pharmacologic activity with increased absorption

Question 20

Ionization

Answer 20

• *MAJOR FACTOR**
• Charged drugs are less lipid soluble and therefore are absorbed less and have less effect on the body
• Interact strongly with water however so it can be carried all around the body

Question 21

Molecular Size + Passive Diffusion

Answer 21

• Drugs’ MW range from very small to extremely large
• Most common drugs range from a MW of 100-1000
• Smaller the MW, the easier it is to passively diffuse

Question 22

Lipinski’s Rule of Five

Answer 22

Orally active drugs usually obey at least 3 of the 4 criteria:

1. Not more than 5H bond donors ( OH & NH groups)
2. Not more than 10 hydrogen bond acceptors (notably N & O)
3. MW < 500
4. log(P) < 5

Drugs can be exceptions to the rule by crossing the membrane via biological transporters rather than diffusion

Question 23

H-Bonds + Bioavailability

Answer 23

• MOST DRUGS ARE ABSORBED THROUGH GUT WALL BE TRANSCELLULAR ABSORPTION**
• Desolvation and formation of neutral molecule is unfavorable if the compound forms many hydrogen or ionic bonds with water
• Don’t want too many H-donors or acceptors else it won’t move from the gut to the blood
• Certain molecules are exceptions like sugars, they move across via special transporters

Question 24

Carrier-Mediated/Active Transport

Answer 24

• Few drugs are absorbed this way
• Example of ones that are are amino acids, levodopa, iron salts, fluorouracil, and propylthiouracil
• Differs from passive diffusion by going against concentration gradients and not requiring energy
• Saturable at high concentrations since there are limited carriers

Question 25

Convective Absorption

Answer 25

- Small molecules (<4 A radius) - Travels through pores (sieving effect) - Saturable