422 exam2 last minute notes

Distributed as powders

B-lactams

epoxides with N

peptides

Allergic/immunogenic reactions

Epoxides

Aziridines

B-lactams

Quinones

Aromatic Criteria

Planar

Fully conjugated

4n + 2

Common aromatic rings

Rings that are not aromatic

5 and 6 membered rings

7 membered rings

Faster metabolism

Lower resonance energy

Amide bonds have partial double-bond character (resonance) —>

planar, trans preferred, restricted rotation

Low stability and low solubility

Planar (sp2)

Rigid

pi-pi stacking (aromatic)

Low Fsp3

Rigid

Low solubility

Lipophilic

High Solubility

Flexible (sp3)

Disrupt packing

High Fsp3

High solubility

Small LogP

Lower brain penetration

More polar (hydrophilic)

Poor permeability

Good solubility

Oral

Large LogP

High brain penetration

More lipophilic

Good permeability

Poor solubility

Topical

Good BBB permeability

LogP 2-4

Small

Nonpolar

Low PSA
Few HBD/HBA

Bad BBB permeability

Large

Polar

Charged

High PSA

Lipinski: Good oral absorption

MW < 500

LogP < 5

HBD < 5

HBA < 10

Lipinski: Poor oral absorption (topical)

MW > 500

LogP > 5

HBD > 5

HBD > 10

Quartenary ammonium compounds

Veber Good bioavailability

< 10 rotatable bonds

PSA < 140

Veber Poor bioavailability

Many rotatble bonds

High PSA
Epoxide

Enthalpy driven

ΔH

Entropy driven

−TΔS

Smaller Entropy Penalty

Few RB

Larger Entropy Penalty

Many RB

Increase binding affinity

Rigid, fused rings

High Plasma Protein Binding

Planar

Lipophilic

Bioavailability decreases when taken with milk/Mg2+/Ca2+

Carboxylic acids

-floxacin

-tetracycline

Few RB

Less entropic penalty

Better oral bioavailability 

Structure determinants

Bond length

Bond angle

Conformation

Hybridization

Conformers differ by

rotation not connectivity

Trans conformers are generally lower energy than

gauche

Synperiplanar =

Synclinal =

Antiperiplanar

0

60

180

Rate the strength of attractions

Charge–charge (ionic) > HB > dipole > VDW

Bioavailability will drop with citric acid due to

Altered ionization/chelation, not transporter inhibition

Azepan

Azetidine

Aziridine

Furan

Indole

Imidazole

Pyridine

Pyrrole

Pyrrolidine

Piperidine

Piperazine

Pyrimidine

Pyridazine

Thiophene

Thiazole

Thiazine

Thiepine

Tetrahydrothiophene

Tetrahydrofuran

Tetrazole

Oxazole

Oxepine

High tPSA

Poor BBB

Small RE

Fastest metabolism

Low logP

Best for oral medications

Large logP

Poor oral absorption

Good topical use

High plasma binding

Large MW

Poor oral absorption

NH Groups

pka=10

pH < pka → protonated (positive)

Carboxyl groups

pka=5

pH > pka → deprotonated (negative)

pH < pka

pH > pka

protonated (positive)

deprotonated (negative)

What cannot be a HBA

Sulfur/Pyrrole

Increase concentration of drug in brain (fatty tissue) and decrease plasma

thiophene

Decrease concentration of drug in brain (fatty tissue)

Pyrrolidine

Trans is more

energetically favorable

PEPT1/PEPT2

LAT1

Large, neutral amino acid

OATPs

more than one carboxylic acid

Passive Diffusion

Non-covalent binding

Irreversible binding

Covalent Reversible binding

same constitution

same molecular formula

same order of atomic connections (connectivity)

same configuration

same 3D arrangement of atoms and the same connectivity

(R vs S)

enantiomers

non-superimposable mirror images (left hand and right hand)

diastereomers

stereoisomers that are not mirror images and cannot be superimposed.

must have the same molecular formula and connectivity, but at least two stereocenters with different configurations

Racemate is composed of

2 non-superimposable mirror images

Newman

Fisher

R and S

D and L

Epimers

Only one chiral center is different