Variants in Drugs Ex

University:
The University Of Western Ontario
Course:
CHEM 1301A | Discovering Chemical Structure
Academic year:

2023
Views:

16

Pages:

3
Author:

Kyuwon J.

● Methamphetamine ○ Low TPSA = 12A ○ Moderate cLogP = 1.8 ■ Better in BBB penetrations ○ Secondary amine (pka ~10) ■ Protonated plasma ■ Free base is partitioned into membrane ● Liphophilic = cross membranes ● brain/plasma ratio in favor on stimulant in chemotypes ● Variant A (metabolic hardening) ○ Slow down oxidative p-hydroxylation ■ Extended exposure = lipophilicity boost ○ cLogP ■ +0.1 - 0.2 ○ TPSA ■ Uncharged 12A ● BBB penetration is still possible ○ Metabolic stability ■ para-F blocks common aromaticity (OH sites) ■ Reduce in first pass + hepatic clearance ○ Problem ■ Longer half life ■ May have time dependent CYP2D6 inhibitions ● May alter target binding ● SERT, NET, DAT ratio must be monitored in chemotypes ○ HLM + NADPH = intrinsic clearance ○ MetID will have loss on p-OH metabolites ○ hERG may have off target panels ■ CV safety ● Variant B (N-dealkylated) ○ Reduce in lipophilicity + shift in transporters ○ Could have shorter t1/2 ○ cLogP drops and TPSA rises ■ More H bond will occur in tautomer ○ BBB ■ Is still penetrable (since TPSA is smaller than 40) ■ Less brain exposure in base ○ PK ■ Faster clearance ■ N-methyl analogs ■ Lesser N-dealkylation pathway ○ Potency may shift ■ Lower ■ N- methyl on CNS stimulation ■ Different stereochemical SAR ● Shows higher activity ● Chiral resolution ● Variant C (Amide isosteres) ○ Reduce in basicity and CNS penetrations) ■ Converting basic amine to amide ● Removing cation characters ● Neutral pKa ● Increase in polarity ○ cLogP similar as before ■ Slightly decreased but TPSA increase to 29A ○ Permeability drop ○ Lower BBB drive compared to original ○ Loss of stimulants ■ Need to design it for aiming on peripheral action ■ Need safety insurance compounds ○ Low permeability ■ Caco-2/PAMPA ○ Microsomal stability + plasma stability ■ Amidase liability ● Side - side properties ○ All remain within RO5 ○ TPSA ranking increase = base p-F (12) ● Rotatable bonds = 2-3 across the set ○ Drug-like zone