SAR Lecture 1 Flashcards
Modification of sulfanilamide to sulfamethoxazole
on previous exam
- increases ability to mimic PABA and inhibit bacterial biosynthesis of folic acid
- increase water solubility of drug molecule and decrease chance of precipitation in urine
- HOW: EWG makes anion @ nitrogen more stable, able to mimic anionic PABA
Physicochemical parameters
electronic effects (hammer constant), lipophilicity (logP/logD),ionization (pKa), solubility, steric effects
biological properties
- PK-related parameters: permeability, absorption, plasma protein binding, Vd, CL, tissue distribution
- PD-related parameters: PK-related parameter, pharmacological activities, drug-target interaction (IC50)
Structural features mimicking natural substances: sulfonamide antibacterial drugs
PABA contains a primary aromatic amine and ionizable COOH that are located para to each other
- sulfisoxazole: pharmacophore
Structural features mimicking natural substances: B-lactam antibiotics
on previous exam
- all active b-lactams MUST contain an ionized COOH and intact B-lactam ring to mimic D-Ala and inhibit transpeptidase
- drug resistance due to B-lactamase–> need for structure modification to prevent inactivation
- steric hindrance confers beta-lactamase resistance but does not interfere with binding of beta-lactam to transpeptidase
HMG-CoA Reducatse
on previous exam
- rate-controlling enzyme of mevalonate pathway–> responsible for cholesterol biosynthesis
- structural requirements: (EX: statins) able to mimic normal substrate, product, and/or intermediate transition state
Enhance Selectivity: Beta>alpha adrenergic activity
-replacing N-methyl group in epi with isopropyl group results enhanced adrenergic B1 and B2 activity
-beta1 receptor requires a catechol ring whereas bulk at N-substituent is allowed for beta2 activity and decreases beta 1 receptor interaction
(homologation)
Adrenalin receptors
selective agonistic or antagonistic effects on specific subtype receptor needed for specific pharmacological activity
- b1 receptor requires catechol ring
- b2 ring allows bulk at N-substituent and decreases b1 receptor interaction
Conformational restrictions: NSAIDS
ortho subs. on lower ring prevents rotation; enhances binding to cyclooxygenase
Conformation restriction: 1,4-dihydropyridine calcium channel blockers
phenyl ring MUST be perpendicular to 1,4-DHP
-ortho and/or meta subs provide adequate steric hinderance that restricts rotation and assures required conformation
EX: nifedipine
Conformational restriction: -exceptional cases
- tamsulosin: selective for alpha-1a receptor
- prazosin: binds to multiple alpha-1 receptor subtypes
Lipinski’s Rule of 5
- number of H-bond donors> 5
- MW>500
- ClogP > 5 or MlogP>4.15
- number of H-bond acceptors > 10
sedating vs non-sedating antihistamine
-diphenhydramine + cyclizine –> sufficient lipid solubility to enter CNS
(sedating)
-fexofenadine and cetirizine –> water soluble
Acid catalyzed degradation
EX: b-lactam antibiotics (penicillin G) cannot be administered orally due to destruction of b-lactam ring in acidic env.
-> degradation can be decreased if EWG present on alpha carbon
estrogen and androgen metabolism
- cannot be administered orally due to C17 hydroxyl groups being rapidly oxidized
- -> to decrease rapid metabolism, add 17a substituent
