1. Chemistry 301 Q1 September 26, 2017: Agenda
Lecture: Schedule for next 2 weeks (including guess appearance and Med Chem software!); continue Med Chem
Lab today (1-4 pm): 1) Continue GC/MS training in small groups (~ 4 people) with Jia today starting at 1 pm; 2) be sure you’re using the online data repository for your ELN, spectra, etc.; 3) please gather 1H and 13C NMR data, IR, melting point, and GC/MS data for your purified intermediates/products – put online!
Next time in lecture: No pre-lab lecture this Thursday, 9/28
Due: Keep working on Chemistry; communicate any problems with Rob . Consult Rob before conducting any new reactions
Homework: Keep working on chemistry
Note: Rob at Agilent tomorrow; this Thursday no pre-lab lecture as Rob is co-presenting webinar on honey bee health research for Agilent that morning (yes lab 1-4 pm; feel free to work in lab at 11:30 am with partner!)

2. Drug metabolism – How does this happen?
We divide metabolism into 2 categories, Phase I and Phase II
Very polar compounds/drugs are quickly excreted by the kidneys; non-polar drugs more successfully absorbed are often metabolized in the liver (it occurs to a lesser extent in the gut wall, blood plasma, and other tissues), specifically by the addition of polar groups to the molecule!
The drug is then more water soluble and is then more likely to face excretion upon passage through the kidneys
Phase I metabolism generally entails oxidation, reduction, and hydrolysis to provide more polar groups
Phase II metabolism involves the attachment of a polar molecule to a group already on the drug or one which was introduced by Phase I metabolism; this makes the drug even more polar and more likely to face excretion

3. Drug metabolism – Phase I
Phase I metabolism generally entails oxidation, reduction, and hydrolysis to provide more polar groups (examples to the right)

4. Drug metabolism – Phase II
Phase II metabolism involves the attachment of a polar molecule to make it even more polar and susceptible to excretion
Glucuronic acid:

5. Blocking metabolism – Blocking groups
We talked last time about decreasing chemical and enzymatic degradation and how metabolism occurs. Let’s move on to blocking/slowing metabolism!
One approach is replacing a hydrogen with a methyl group to block the introduction of a polar hydroxyl group that allows Phase II conjugate addition and elimination
This approach was used with the oral contraceptive megestrol acetate
Figures are from G. Patrick’s “An Introduction to Medicinal Chemistry” 5th Ed.

6. Blocking metabolism – Blocking groups continued
Another approach to slowing metabolism involves the introduction of a fluorine atom at the para-position of an aromatic ring
The compound CGP was in development as an enzyme inhibitor of EGF (epidermal growth factor – a protein that stimulates cell growth), but it was determined that it was metabolized by oxidation at the para-position. How determined?
F was substituted to address!
Deuterium is also thought to
have potential! (C-D vs. C-H
bond strength)

7. Blocking metabolism – Functional group substitution
Many other common groups are susceptible to Phase I/II metabolism; substituting other groups for these is part of a broader strategy
Methyl groups on aromatic rings can be oxidized to carboxylic acids. Aliphatic and aromatic C-hydroxylations, N- and S-oxidations, O- and S-dealkylations, and deaminations are common
An example was the replacement of a methyl group by a chlorine in the antidiabetic tolbutamide to produce a longer-lasting chlorpropamide
Other examples include
substitution of other bioisosteres
for esters, etc.

8. Blocking metabolism – Group shifts
What if the group that makes a drug like molecule susceptible to metabolism is necessary for its interaction with a binding site in a target enzyme?
We can either temporarily protect that site by making a “prodrug” or “shift” the group within the existing skeleton

9. Blocking metabolism – Group shifts
What did we do here with the asthma drug, salbutamol? How did it help?

10. Blocking metabolism – Ring variation, ring substituents
Aromatic rings that are susceptible to metabolism may be stabilized by adding N atoms to decrease electron density in the ring
This may also decrease the susceptibility of a ring methyl group to metabolism

11. Enhancing metabolism!
If a drug is too stable and resistant to metabolism, you may need to increase its metabolism to prevent toxicity or long lasting side effects

12. “Self-destruct” drugs
Cromakalim is an anti-asthmatic drug that is effective when inhaled into the lungs, but it can cause cardiovascular side-effects if it is absorbed into the systemic blood supply
There are ways to address this!