Youngjae You Chemistry Exam 4

Modification of Sulfanilamide → Sulfamethoxazole

1. Increases the ability to mimic PABA and inhibit bacterial folic acid synthesis

2. Increases water solubility of drug and decreases urine precipitation

Pharmacophore

Minimum structural requirements for drug activity

B - Lactam Antibiotics SAR

• must contain ionized C. Acid

• must contain intact B-Lactam ring

B - Lactam Antibiotics SAR to prevent B-lactamase inactivation

• Steric hindrance & doesn’t interfere with binding to transpeptidase

HMG-CoA Reductase SAR

• Mimics substrate / product / transition state

• 3 - methyl group NOT required for inhibitory effect

BONUS: “Corpora non agunt nisi fixate” → binding interactions are critical to MOA of drugs and selectivity

Paul Ehrlich

Epinephrine and Selective B Agonist SAR

• replacement of N-methyl group with isopropyl group results in no A adrenergic activity but enhanced B1 and B2 activity

Separation of B1 and B2 activity SAR

• B1 receptor → requires catachol ring

• B2 receptor → requires bulk N-substitution and decreases B1 receptor interaction

B1 Receptor Antagonism SAR

• Replacement of catachol ring with para substituted phenyl ring changes it to antagonistic activity

NSAID Conformational Restriction

• Ortho substituents on lower ring cause conformation restriction and prevent rotation

• Enhances binding cyclo-oxygenase binding

CCB Conformational Restrictions

• Phenyl ring must be perpendicular to the 1,4 - DHP

• steric hindrance restricts rotation and assures required conformation

ACE Inhibitor SAR

• Needs FG that can interact with zinc atom on enzyme active site

Lipinski’s Rule of 5

Sedating vs. Non-sedating Antihistamines

• Diphenhydramine & cyclizine have lipid solubility enough to cross the BBB whereas fexofenadine & certirizine don’t

  • contain alcohol groups that make them more water soluble

Metabolism of Estrogens & Androgens SAR

• cannot be administered orally because they are rapidly oxidized

• 17a substituent blocks the C17 Hydroxyl from oxidation and allows these drugs to be administered orally

Adverse reaction of Cefotetan

• The MTT group was associated with acute alcohol intolerance and serious bleeding

• Once linked to this FG, drugs containing MTT were discontinued

Tetracycline & Fluoroquinolone Drug Interactions

• dicarbonyl groups can chelate with Ca, Mg, Al, and Fe in the gut

• this leads to very poor water solubility and decreased absorption

• do not take vitamins/dairy that contain these metal ions

Water/Lipid solubility of Azole Antifungal Agents

• Imidazole ring is pH dependent, meaning increasing pH can decrease ionization and water solubility, from DDI

• The two triazole rings are not pH dependent and therefore safer to use in every situation

Acid / Base Plasma Protein Displacement Interaction

• Acids

  • Bind substantially to plasma albumin through ionic interactions

• Bases

  • Bind moderately to a1-acid glycoprotein

  • may be be clinically relevant

Lead Compound

Lead Compound Discovery

• Virtual screening

• Fragment-based drug design

• Drug repurposing

Phenothiazine Antipsychotics SAR

• Conformational restriction requires aliphatic amine to lie on the same side as the chlorine on the aromatic ring

• Z isomer more potent then E isomer

ARB SAR

• substitution of C. Acid with another acidic group such as tetrazole gives several benefits

  • Tetrazole less likely to undergo metabolism

    • is more lipophilic

    • enhances oral absorption

    • allows for better charge distribution

      • enhances stability and binding interaction to receptor

Sulfonyl Urea variation of FG SAR

• para methyl is rapidly metabolized

• changing the group to a chloro FG prolongs half life

Lincoasamide variation of FG SAR

• Replacement of -OH group with -Cl group

  • enhances lipophilicity

    • crosses bacterial membranes better

  • better oral absorption

Zidovudine Inhibition of Reverse Transcriptase SAR

• Zidovudine mimics nucleic acids but with a removed 3’ OH group for an azido group inhibiting function

Sulfonamide Anti-metabolite Variation of FG SAR

• Sulfisoxazole contains groups mimicking PABA but with an additional group that inhibits bacterial enzymes

Isosteres

• Compounds and Groups of atoms that contain same number and arrangement of electrons

• Limited and not very applicable to drug molecules

Grimm’s Hydride Displacement Law

• organized groups of atoms according to valence atoms and allowed for different number of atoms

Erlenmeyer Isosteres

• Expanded the table of isosteres

• considered:

  • ionization

  • neutral molecules

  • water solubility

  • lipid solubility

  • electronegativity, steric size, shape

Friedman Bioisosteres

• Functional groups or molecules that have similar chemical and physical properties and produce broadly similar biological properties

Anti-Arrhythmic isosteric replacement

• Ester undergoes rapid hydrolysis, poor F, short duration

• N substitution decreases metabolism, and increases F

Nonclassical Isosteres

• Do not follow the guidelines set by Grimm and Erlenmeyer

• Larger in size, rarely have same # of atoms, and can vary in valence electrons

Homologation

• Extending a hydrocarbon chain by successively adding methylene groups

• Increases size and lipophilicity of FG

• Ex. N - Homologation of epinephrine makes it beta selective

In Vitro, in Vivo, In Silico

• Outside an organism, like a petri dish

• Inside living organism

• On a computer

In Vivo and In Vitro, activity is dependent on …

Concentration

PK Route

IV Bolus

PK Route

IV Infusion

PK Route

Oral tablet or capsule

PK Route

Enteric coated tablet or capsule

PK Route

Transdermal patch

______ is the driving force for drug activity / response

Drug Plasma Concentration

Bioavailability

Fraction of initial dose that reaches circulation after first pass effect

F = AUC oral / AUC iv

Volume of Distribution (Vd)

• Proportionately relates amount of drug in body with measured plasma concentration

• High Vd = high tissue distribution

• weak basic groups, low plasma binding, high lipophilicity, low ionization rates

Clearance (Cl)

Volume of plasma which drug is totally removed over a specified period of time

PBPK model vs Conventional Compartment Model

• PBPK → real tissue and blood flow, more realistic

• Compartment → more simplified, grouped tissues

BONUS: Occupancy theory, relationship between concentration and target occupancy

A.V. Hill

BONUS: Response is directly proportional to occupancy

A.J. Clark

Hill Equation

Measures the relationship between concentration and activity

• Emax, EC50, C, etc..

Hammet Equation

Relates the electronic effects of substituents on the reactivity of aromatic ring compounds

Plasma Protein Binding - Weak Bases

A1-Acid Glycoprotein

• becomes protonated inside tissues/lysosomes

• trapped in tissue = high Vd

Plasma Protein Binding - Weak Acids

Albumin

• negative charge attracts albumin binding

• Stays in plasma = Low Vd

Relationship between LogD and renal clearance

High LogD = drug tissue permeable and is reabsorbed = low renal clearance = high non-renal clearance