1. Chemistry 301 Q2 Tu/Th November 30, 2017: Agenda
Lecture: 1) Case Study project, 2) Alternate path to some of our targets, 3) brainstorming on WuXi procedure yield issues, 4) more Med Chem
Lab: Keep rocking 
Next time: Skype with Ben/DNDi and perhaps WuXi to discuss procedure optimization; next Thursday Skype with Tamsin
Homework: Be sure to tell Rob if you need chemical x/y/z, let Rob know if he can help run any reaction!
NB Rob here all this week but very busy with a visitor and Group Meeting tomorrow late morning and during afternoon

2. Case Study Project
See Moodle!

3. Alternate path/s to targets
More cool chemistry!

4. Aminopyrazole
Route 1:
The robust route to prepare 4-alkyl-aminopyrazole if the corresponding alkyl nitrile is available.

5. Aminopyrazole Route 2: Route 3:
The robust route to prepare 4-halo-aminopyrazole.

6. Aminopyrazole
Route 4:
4-phenyl-aminopyrazole.

7. Aminopyrazole
Route 5:
4-heterocycl-aminopyrazole via C-H coupling.

8. Aminopyrazole Route 6: 4-heterocycl-aminopyrazole via Suzuki coupling.
The Suzuki coupling conditions was selected by WuXi Kits Screening.

9. WuXi procedure optimization
Let’s put our heads together!

10. Fundamental Med Chem topics -- Continued

11. Solubility
Influenced by hydrophilicity/hydrophobicity of the molecule!
Too polar (orally administered) prevents passage across cell membranes in gut wall
Too greasy (orally administered) won’t be absorbed well in gut but rather dissolved in fat globules in gut
We measure the hydrophobic nature of a drug with the partition coefficient (P), which measures relative distribution of a drug in n-octanol/water
Hi P value indicates a relatively more hydrophobic compound; log P values are used typically to measure hydrophobicity

12. Solubility/Numerical Representations
Examples of molecules with low and high log P values
Remember, we try to avoid very hydrophilic and very hydrophobic compounds for oral administration
Do these values make sense?

13. Solubility – Varying N-alkyl substituents to vary pKa
We may need to alter the structure of a drug with a pKa outside the range of Why?
We can add a) extra N-alkyl groups or b) larger N-alkyl groups to increase basicity
BUT! What is the potential problem there? What additional “trick” can you see to the right in “PRO 3112”?
- High or low pKa tends to lead to greater ionization and more difficulty of absorption of compound through cell walls
Amidine is more basic than PRO 3112 as 3112 “wraps up” the basicity without a loss of activity
Adding N-R groups increases electron-donating effect to increase basicity but more bulky groups prevents interaction with water

14. Solubility – how can we change it?
To make a molecule less polar, we can “mask” polar groups by, e.g., converting an alcohol or phenol to an ether or ester; a carboxylic acid to an ester or amide; 1˚ or 2 ˚ amines can be converted to amides or 2˚ or 3˚ amines. Be careful, though!
To make a molecule more polar, we can add polar groups!
Next time… A bit more on solubility, on to metabolism

15. Solubility – Changing by varying hydrophobic substituents … we can:
Increase hydrophobicity by a) adding alkyl groups in the carbon skeleton or b) increasing the size of existing alkyl groups
Decrease hydrophobicity by a) decreasing the size of existing alkyl groups or b) removing them
Increase the size of one existing alkyl group and decrease another
Add –F or –Cl (rarely –Br or –I) to increase hydrophobicity

16. Solubility – Varying aromatic substituents to vary pKa
We can change the pKa of an aromatic amine or carboxylic acid by adding electron-donating or withdrawing substituents to the ring!
Remember the position of such a substituent can affect a more distant group through induction and/or resonance
It was found that the substitution of a –NO2 group for a –Cl group in the development of oxamniquine (right) improved activity, and a pKa change was thought to be involved. How?

17. Solubility – Using “bioisosteres” for polar groups
Bioisosteres are functional groups that have similar chemical or physical properties but which may improve such characteristics as bioavailability, toxicity, etc.
Medicinal chemists use these frequently!
One example is the substitution of the tetrazole group for a carboxylic acid
Both have an acidic proton and exist in ionized form at pH 7.4, but the tetrazole is 10x more lipophilic than a carboxylate anion so drug absorption is increased!
Some cool acid
isosteres!

18. Fighting chemical and enzymatic degradation – Steric shields (from Star Wars?)
We talked earlier about the body’s ability to break down drugs. Is there anything we can do to prevent/decrease/eliminate this degradation?
Do we want to eliminate it?
As you can imagine, esters and amides are readily hydrolyzed in our gut; what if we don’t want that to happen to a drug?
We can put in a bulky group – a steric shield – near the functional group to make hydrolysis more difficult!
Figures are from G. Patrick’s “An Introduction to Medicinal Chemistry” 5th Ed.

19. Fighting chemical and enzymatic degradation – Use of bioisosteres
Remember, the key to bioisosteres is that they are groups substituted for other groups that preserve biological activity but improve some other aspect of the drug
We can replace the –CH3 in the ester below with an –NH2 to give a carbamate; it has the same valency around the central atom and size, BUT the electronics are different! How? Why does that matter?
You might also use an amide. Such bioisosteric replacements may be specific to certain categories of drugs.
You can also manipulate the electronic effects (inductive effects) of, e.g., esters to “tune” the ease of their hydrolysis

20. Fighting chemical and enzymatic degradation – Steric and electronic modifications teamed-up!
What has been changed in the short-acting local anesthetic Procaine to produce the longer acting anesthetic Lidocaine?
Is there a place for both?

21. 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

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

23. 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:

24. 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.

25. 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)

26. 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.

27. 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

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

29. 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

30. 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

31. “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!