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!

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

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)

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

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

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?

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.”

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?

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?

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?

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

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

Histamine

N

N

H

NH2

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

1st Generation Antihistamines (H1)

N

S

CH3

CH3

NCH3

Promethazine (Phenergan) Diphenhydramine (Benadryl)

ON

CH3

CH3

Clemastine (Tavist)

O

Cl

H3C

NCH3

Chlorpheniramine (Chlortrimeton)

N

N

CH3

CH3

Cl

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?

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

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!!!

2nd Generation Antihistamines (H1)

Fexofenadine(Allegra)

HO

NOH

CH3C CO2H

CH3N

N

Cl

O OCH2CH3

Loratidine(Claritin)

N

OOH

O

N

ClCetirizine(Zyrtec)

Any Structural Differences?

Hydrophobic, planar functional groups Short bridge to ionizable functional group Ionizable functional group (amine) And…..

– Hydrophilicity that is ionizable!

Does Patient Experience Change?

What happens to the therapeutic effect?

What happens to the side effect profile?

What happens to patient compliance?

Back to Indigestion…

ON S

N

CH3

H3C

HCNO2

NCH3

H H

Ranitidine(Zantac)

N

S

SN

NSO2NH2

CH3

NH2N

NH2

H

Famotidine(Pepcid)

N

CH3

H3C

S

NO2HC

CH3NN

N

S

H H

Nizatidine(Axid)

N NH

H3CS

N

NCN

NCH3

H H

Cimetidine(Tagamet)

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

Model: H2 Receptor Binding

Hydrogen Bonding

Bidentate Binding

Small HydrophobicPocketSmall Hydrophobic

Pocket

Hydrophobic Pocket for Aromatic Rings

ComplementaryAnionic Binding

Pocket

O

O

N

S

S

N

NH2

H3N

NH

CH3

SO2NH2N

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?

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!

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

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.

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….

CH3O

CH3

O

O-Na+

Naproxen Sodium(Anaprox, Aleve)

Non-steroidal Anti-inflammatory Drugs

O CH3

CO2H

Ketoprofen (Orudis)

N

O

H

CO2H

CH3

H3C

Etodolac(Lodine)

Acetaminophen(Tylenol)

N CH3

H

OHO

CH3

O

CH3O

Nambumetone(Relafen)

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

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.

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?

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

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

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!!!

COX-2 Selective Inhibitors

Rofecoxib(Vioxx)

O

S

O

O

H3C

O

Valdecoxib(Bextra)

NO

S

O

O

H2NCH3

Lumiracoxib(Prexige)

CO2H

NH

ClF

H3C

N N

S

O

O

H2N

H3C

CF3

Celecoxib(Celebrex)

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

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

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)

THANK YOU!!

Any Questions? Thoughts? Suggestions?