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Diverse Disciplines in Chemistry. Medicinal Chemistry in the Practice of Pharmacy. Robin M. Zavod, PhD. First: Who is Sitting Next to You?. Dust off the Rust! Rev up the Brain Cells! Get the pie-hole working again! ICE BREAKER!

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Diverse Disciplines in Chemistry

Medicinal Chemistry in the Practice of Pharmacy

Robin M. Zavod, PhD


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First: Who is Sitting Next to You?

  • Dust off the Rust!

  • Rev up the Brain Cells!

  • Get the pie-hole working again!

  • ICE BREAKER!

    • Work with a group of 3-4 people to identify as many Wacky Wordies as you can!


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Second: What’s the Plan Tonight?

  • Careers in Chemistry

  • Introduction: What is Pharmacy? What is Medicinal Chemistry?

  • Examples: How is Medicinal Chemistry used in the Practice of Pharmacy?

    • Histamine (receptors)

    • Cyclo-oxygenase (enzymes)


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What is Pharmacy?

  • Past: Dispense Medications

    • Pharmacist isn’t involved with patient education

  • Present: Providers of Pharmaceutical Care

    • Dispensing role de-emphasized

    • Pharmacists are drug information specialists

  • Future: Individualized Medicine

    • Genetic information directs medication selection


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What is Medicinal Chemistry?

  • Drug Mechanism of Action

  • Structure Activity Relationships

    • Drug structure predicts biological activity

  • ADME: Absorption, Distribution, Metabolism, Excretion

    • Tweaking functional groups and formulation

  • Interactions: Biological Target for Drug Action

    • Optimization of drug potency


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Melding the Two Disciplines

  • If Pharmacists are the drug information specialists, what kind of information do they need to know?

  • If Medicinal Chemists are the creators of new drug entities, what kind of information do they need to know?


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Patient Case #1

E.M., a 43 year old mother of two teenage boys, walks into the pharmacy and says "Getting my two boys off to school this fall will be a challenge. It is more than my head can take at that time of the morning, not to mention my stomach! I can’t believe how bad the allergy season has already been.”


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Allergies: Sequence of Events

  • Allergens elicit release of histamine from mast cells

  • Histamine receptors are activated

  • Physiological responses are generated

    • Hives/Rash

    • Runny nose/itchy eyes

    • Wheezing

  • What does it take to stop this process?


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Indigestion: Sequence of Events

  • Release of histamine into GI tract

    • Overeating, excess consumption of alcohol

    • Stress; Some medications

  • Histamine receptors are activated

  • Physiological response is generated

    • Increased gastric acid production

    • Irritation/ulceration of mucosal lining of the stomach

  • What does it take to stop this process?


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Are all Histamine Receptors the Same?

  • Based on your own knowledge, do either of these scenarios make sense?

    • Take a dose of Benadryl® to settle your stomach?

    • Take a dose of Pepcid® to stop your eyes from itching and your nose from running?

  • Benadryl® = antihistamine right?

  • Pepcid® = antihistamine too?


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Chemists to the Rescue!

  • All histamine receptors are activated by histamine (histamine = agonist)

  • Activation of histamine receptors produces different biological responses

  • Histamine receptors: H1, H2, H3 and now H4!!

  • Location of receptors vary

    • Peripheral tissues, CNS, GI tract


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What does Histamine look like?

  • Imidazole – planar

  • Bridge – carbon based

  • Ionizable group (amine)

  • Acid/Base Chemistry

    • Drug ionization

  • Binding Interactions:

    • Ionic or ion dipole

    • - stacking


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What is an “Antihistamine”?

  • What happens when a drug binds to a histamine receptor and prevents histamine from binding?

  • Therapeutically: Benadryl® = Histamine blocker (antagonist)

  • Chemically: H1 receptor antagonist

  • Therapeutically: Pepcid® = Acid blocker

  • Chemically: H2 receptor antagonist


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1st Generation Antihistamines (H1)


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Structural Eval: Pharmacophore

  • Hydrophobic, planar groups

  • Ionizable functional group present

  • Defined distance between hydrophobicity and ionizable functional group (amine)

  • Additional bulk allowed

  • What do these agents mimic?

    • Why don’t they activate the histamine receptor?


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Therapeutic Effects Observed

  • Secretions dry up

  • Hives/rash stop itching

  • Eyes stop itching/burning

  • Side Effect: Dry mouth

  • Side Effect: Sleepiness/lethargy

  • Compliance Issue: q4-6H dosing


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Where do Side Effects come from?

  • Biology: Receptors located in both peripheral tissues and in the CNS

  • Chemistry: H1 receptor antagonists aren’t geographically selective

  • From a biological and structural perspective, why do we experience these side effects?

  • Can Medicinal Chemists fix this problem?

    • YES!!!


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2nd Generation Antihistamines (H1)


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Any Structural Differences?

  • Hydrophobic, planar functional groups

  • Short bridge to ionizable functional group

  • Ionizable functional group (amine)

  • And…..

    • Hydrophilicity that is ionizable!


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Does Patient Experience Change?

  • What happens to the therapeutic effect?

  • What happens to the side effect profile?

  • What happens to patient compliance?



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Structural Eval: Pharmacophore

  • Planar heterocycle

    • Not necessarily hydrophobic

  • Bridge to ionizable functional group

  • Ionizable functional group (amine)

  • Bridge to functional group capable of H-bonding with receptor

  • Small hydrophobic groups


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Model: H2 Receptor Binding


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H2 Receptors and Antagonists

  • Receptors located exclusively in the GI tract

  • Remember: Activation of H2 receptor causes increased production of gastric acid

  • Drugs are called “acid blockers”, what are they really?

  • No H2 receptors located in the periphery or in the CNS, so there aren’t any side effects, right?


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Metabolism: Adverse Drug Reactions

  • Mostly Drug-Drug Interactions

    • Most significant with cimetidine (Tagamet®)

    • Serious problem in pharmacy (OTC meds)

  • Is there a structural basis for this?

    • Yes! Imidazole interferes with metabolic enzymes

  • Can you design out this problem?

    • Yes! Replace imidazole with a bioisostere!


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Medicinal Chemistry Roles

  • Design more potent derivatives

    • Decrease dosing frequency

    • Increase patient compliance

  • Design more selective analogs

    • Decrease side effect profile

    • Decrease adverse drug reactions


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Patient Case #2

A refill prescription for naproxen sodium (Anaprox; Aleve) was called in by DR, a patient who is training for an upcoming 10K race. The last time he picked up his meds he complained that even though he had dropped his weekly mileage, he was still experiencing mild pain in his left knee between doses of naproxen. Today DR stops by the pharmacy to pick up his refill along with several gallons of a popular “sports drink” that contains a high concentration of sodium citrate. While paying for his medication you ask him, “How much of that stuff do you consume?” DR says that he consumes nearly a gallon of the “sports drink” daily.


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Excretion: Drug-Food Interaction

  • Information to Consider:

    • Drug pKa = 4.2

    • Normal urine pH = 5-6

    • Sport drink basifies the urine to ~7.5

  • Decreased therapeutic effect observed – Why?

  • Can Medicinal Chemists fix this problem?

    • Uh….



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Structure Activity Relationships

  • Acidic functional group is required (“no”)

    • Carboxylic acid bioisosteres allowed

  • One carbon bridge (critical length)

  • Planar functional group

    • Aromatic hydrocarbon or heterocycle

  • Relafen®: bioactivation to acidic metabolite required


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Additional Patient Information

DR calls the pharmacy with a question that he forgot to ask you. He wants to know if it is “ok” for him to take a couple of Tums® or some Maalox® for the moderate stomach upset that he gets when he takes the naproxen sodium on an empty stomach.


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Absorption: Acid/Base Chemistry

  • Information to Consider

    • Normal stomach pH = 1

    • Drug pKa = 4.2

    • FDA Definition: The antacid product must neutralize at least 5 mEq of acid per recommended dose and must maintain a pH of 3.5 for 10 minutes in an in vitro test.

  • Will the antacid have any effect on drug absorption? What do you tell the patient?


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Inflammation: Target for Drug Action

  • Cyclo-oxygenases (COX-1, COX-2 and COX-3!!)

    • Catalyze biosynthesis of prostaglandins PGG2, PGH2, PGE2 from arachidonic acid

  • PGG2 roles

    • Mediates response to pain

    • Mediates inflammatory response

  • PGH2 role

    • Mediates response to pain

  • PGE2 role

    • Protects gastroduodenal mucosa by several mechanisms


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Therapeutic Effects Observed

  • Decreased or modulated pain response

    • Inhibition of COX-1 and COX-2 enzymes

  • Improved joint mobility

    • Inhibition of COX-1 and COX-2 enzymes

  • Decreased patient compliance (over time)

    • Side Effect: GI upset


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Side Effect: GI upset

  • What is the cause of this side effect?

  • Can Medicinal Chemists fix this problem?

    • COX-1 vs. COX-2 enzymes

    • Active/catalytic sites are nearly identical

    • Physiological functions differ considerably

  • Can we design COX-2 selective inhibitors?

    • YES!!!



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Did we solve the problem?

  • Continued GI upset possible

    • We achieved Selectivity not Specificity

    • Contraindicated in patients on Warfarin®

  • Allergy Potential

    • Fraction of population allergic to “sulfa” drugs

    • Some COX-2 selective agents have sulfonamide


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Medicinal Chemistry + Pharmacy

  • Drug Structure Activity Relationships

    • Potency

    • Dosing frequency

  • Selectivity vs. Specificity

    • Side effect and adverse drug effect profiles

  • ADME

    • Functional group manipulation

    • Drug-drug, drug-food interactions

    • Metabolic interference


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Acknowledgements

  • Dr. Jeffrey Jankowski (ACCA Coordinator)

  • Drs. Shridhar Andurkar, Robert Chapman, Jeffrey Christoff and Bruce Currie (MWU-CCP Faculty)

  • Ms. Angela Karash, MSc. (Teaching Assistant)


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THANK YOU!!

Any Questions? Thoughts? Suggestions?