1. Chemistry 301 Q2 Tu/Th November 7, 2017: Agenda
Lecture: 1) NMR follow-up – reminder of wonderful trace impurities paper, 2) synthesis of original “hit”, 3) ADME(T) quick intro in advance of Thursday’s Skype with Ben Perry/DNDi, 4) some comments on technique in our lab
Lab: 1) target assignment/choice with Rob – available to choose at 1 pm online under today’s date as a Google Sheet link, 2) work in lab
Next time: Thursday lecture will be an intro to the drug discovery effort background for your molecules by Ben P.
Homework: 1) look into what the data on Ben’s slides mean, 2) work on synthesis assignment
NB Rob here Thursday all day and Friday (until about 3 pm); if you need me tomorrow

2. NMR follow-up

3. Hit Finding
Original hit was identified by screening a diverse set of compounds from the Pfizer compound file
Weak axenic (extracellular amastigote) potency with poor translation to intracellular amastigote activity
Poor metabolic stability
AlogP 3.0, logD 3.2, PSA 100
HLM Clint 67 µL/min/mg
HamLM Clint 191 µL/min/mg
J. Med. Chem. 2015, 58, 9615

4. Let’s talk about some fundamental Med Chem topics!
And importantly what is our context?

5. Some Key Med Chem Concepts
Pharmacokinetics: how a drug is absorbed, distributed, metabolized, and excreted (aka ADME). Sometimes you’ll hear the term ADMET or ADME/Tox.
E.g. “a patient has been given an intravenous injection of a post-operative painkiller. The kinetics of pain killers are important as pain relief is closely related to plasma concentration.”
(what the body does to the drug!)
Pharmacodynamics: “the study of how a drug binds to its target binding site and produces a pharmacological {biological effect on an organism or a part thereof} effect”
E.g. “the exposure of tumor cells in vitro to varying doses of a new agent to evaluate its dose-response relationship, or a Phase I clinical trial to define the maximally tolerated dose and dose-limiting toxicities in patients.”
(what a drug does to the body!)

6. A…D…M…E…
Absorption
If orally administered, drug needs to be hydrophobic enough to interact with the fatty cell membranes of the gut wall but hydrophilic enough to resist dissolution in fat globules in gut
Distribution
Once absorbed, drugs enter blood supply – arteries, veins, capillaries. Drugs can pass through pores in capillaries into tissues and aqueous environment around body’s organs. They can act on their target there or may need to enter individual tissue cells to act. Watch out for plasma protein binding and fatty tissue absorption! (Also BBB, placenta, DDIs.)
Metabolism
Enzymes degrade/modify drugs so they’re excreted more readily. Metabolites may be even more active than drug (prodrug approach)! Metabolites must now be identified (including stereochemistry! and biological activity!) before approval.
Excretion:
Blood/kidneys/urine/bladder principally; Blood/liver/bile duct/intestines; Lungs: volatile drugs, metabolites; Skin by sweat!; Less so saliva, breast milk; reabsorption is possible in this process

7. Hit Finding
Original hit was identified by screening a diverse set of compounds from the Pfizer compound file
Weak axenic (extracellular amastigote) potency with poor translation to intracellular amastigote activity
Poor metabolic stability
AlogP 3.0, logD 3.2, PSA 100
HLM Clint 67 µL/min/mg
HamLM Clint 191 µL/min/mg
J. Med. Chem. 2015, 58, 9615

8. Lead Optimisation (1) ‘Sweet spot’: Proved to be a successful approach
Key areas for focus – improving potency, metabolic stability and solubility
‘Sweet spot’:
logP = 2–3.5
IC50 ≤1 M
HLM Clint <12–25 L/min/mg
Proved to be a successful approach
Optimised leads identified with improved profiles

9. Always use the correct technique for your safety and best results!
Technique updates!
Always use the correct technique for your safety and best results!

10. Read all hazards on chemicals
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11. Microscale We will be running reactions typically on 100 mg or less!
This might be on the new side for you
It’s totally doable, but you need to always think about how you can adjust your technique for the best results!
A few tips: 1) if you’re scaling down a lit procedure, think about your choice of glassware and, e.g., the need to use more solvent; 2) think about potential losses at every stage and minimize these (e.g. recover NMR samples in solvents that permit, use the proper size column, etc.); 3) don’t ever compromise safety (e.g. if you run your rxn in a vial, think about how to do it safely without creating a truly closed system)

12. Dispensing solids/liquids
Please weigh all solids and dispense all liquids in the hood
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13. Air sensitive reagent handling
Please perform all of your reactions in dry glassware (you can use the drying oven) and under an Ar balloon atmosphere unless your reaction specifies otherwise
Never use or heat a system that is closed!
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14. Hot plates and temp sensors
In your hood unplug all hotplates, stirplates, variacs, and all other electrical devices when not in use
If you use a combination temperature probe/hot plate, see Rob for special instructions – do NOT remove probe from oil bath while plate is on/plugged in
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15. Time Management
Sounds like a pretty simple concept, but you really need to think about it in terms of how to maximize your time in the lab
Remember, you are in pairs: how can you both be doing something productive at all times
Can you come in as a pair the evening before on a Monday or Wednesday and set up a reaction safely that will be all ready to work up the next day when we meet for Superlab?
Should you start B before F or vice versa? Should you work on them simultaneously?
Is there such a thing as trying to do too much chemistry at one time?

16. Laboratory Notebooks
Please use Rob’s template for an electronic notebook
As you gather data for each successful reaction, make sure your procedures and spectral data are recorded in your electronic notebook in the form you see in Mowbray’s article (in J. Med. Chem. format)
Print out a hard copy for each experiment when you are finished with it and put in your notebook as a back-up