SAR Levers on Scaffolds

University:
The University Of Western Ontario
Course:
Pathology 3500B | Human Pathology
Academic year:

2023
Views:

143

Pages:

3
Author:

Kyuwon J.

● N-methyl-1-phenylpropan-2-amine ○ RO5 ■ MW = 149.24 ● Less than 500 therefore edible ■ H bond donors = 1 ● Less than 5 ■ HBA = 1 ● Amine N ■ Clogp = 3 (freebase) ■ TPSA ● 12 A = very low ■ PKA = 9.8-10.2 ■ Free base = lipophilic ● Can cross BBB ● Low TPSA ● Favors CNS exposures ● Aromatic ring ○ Hydrophobic ○ Pi-stacing possible used as anchor ○ Para-positioning = common site for SAR tuning ■ p-MeO ■ p-F ■ p-OH ● B-phenoethylamine / amphetamine core ○ Catecholamine mimetics ○ Distance on amine to aryl (around 2 carbons) ● A-substituted carbons ○ S vs R enantiomers ○ S ■ More CNS stimulants are activated ● Secondary amine (in N-Methly) ○ Lipophilicity increase ○ CNS penetrations with primary amine = N-dealkylation ● Benzylic positions ○ Soft metabolics ○ Oxidation side chains PK implications ● BBB penetrations ○ Active in low TPSA ■ Moderate cLogP ■ CNS activated ● Ionization = as protonation in plasma membrane ○ Forms HCL = increase in aqueous solubility = dosage forms ● Metabolism ○ N-dealkylation => amphetamine ○ Aromatic p-hydroxylation => p-hydroxy metabolites ○ Sie chain oxidation +diamination => benzoic + hippuric acid derivatives SAR levers on Scaffolds ● N- substitution ○ Primary amide will decrease lipophilicity ■ Alter transporter + target profile ○ Bulkier N-alkyls ■ Able to shift potency + selectivity ■ If too bulky, will loose in activity and caus slower clearance ● Para-ring substituents ○ p-OH and P-MeO ■ Increase in polarity ■ Bioisoteres of catecholamines ■ Change MAO +CYP liability ○ p-F and pCF3 ■ Blocks oxidations ■ Increase in lipophilicity ● A-substituents ○ S-perfered for stimulants ○ fixed stereochemistry = increase in potency + selectivity ● Converts amide -sulfonamide - urea ○ Isosteres ○ Suppress basicity + reduce in CNS penetration ■ Preferably when agents are desired Liabilities ● High CNS exposures ○ Low TPSA + moderate cLogP ● Metabolic soft spots ○ Benzilic + N-methyl sites ■ Reactive metabolites ● Potent catecholaminergic activity ○ Abuse potential in chemotypes