STRUCTURE-ACTIVITY

RELATIONSHIP
PART III

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GASTROINTESTINAL
DRUGS
!  Histamine H2-Antagonist
!  Therapeutic application in the treatment of acid-peptic
disorder including:
"  heartburn
"  gastroesophageal reflux disease (GERD)
"  gastric and duodenal ulcers
"  gastric pathologic hypersecretory disease such as Zollinger-Ellison
syndrome
!  Combination with Histamine H1 antihistamine for:
"  urticaria
"  pruritis
!  CIMETIDINE
"  Gastricantisecretory agent (tx of duodenal ulcer)
"  Short acting
"  60%-70% bioavailability
"  Plasma half life 2 hrs.
"  with antiandrogenic activity
(imidazole – gynecomastia)
"  Decrease absorption of azole (shld be taken 2hrs before cimetidine
administration)
"  Antacid + Cimetidine ( Antacid administer 1 hr before)
!  FAMOTIDINE
"  Competitive inhibitor of histamine H2 receptors
"  Potency greater than Cimetidine
"  Inhibits basal and nocturnal gastric secretion as well as secretion
stimulated by food.
"  Treatment for :
"  gastroesophageal reflux disease (GERD)

"  gastric and duodenal ulcers

"  gastric pathologic hypersecretory disease such as Zollinger-

Ellison syndrome
"  Thiazole ring
"  Bioav 35%-45%
 Histamine 2-Receptor Antagonists

!  RANITIDINE (Zantac)
"  More potent than cimetidine
"  Less potent than famotidine
"  Bioavailability 50%
"  Not affected by food
"  Affected by antacids (take 1 hour before)
"  Furan ring with nitrogen containing substituent
"  Long lasting and 10x the activity of Cimetidine
 Histamine 2-Receptor Antagonists

NIZATIDINE (Eli Lilly)

•  More potent than cimetidine

•  Excellent bioavailability
(>90%)
•  equipotent with ranitidine and differs by the
substitution of a thiazole-ring in place of the furan-ring
in ranitidine
 Proton Pump Inhibitor

Pumping of protons in the lumen of the stomach –

FINAL step in acid secretion

1972 – Swedish medicinal chemist discovered

pyridylmethylbenzimidazole sulfides
capable of producing H+, K+, ATPase
or PPI s
 Pantoprazole

!  GERD
!  treats high levels of acid in the stomach caused by a
tumor (such as Zollinger-Ellison syndrome)
!  6-(difluoromethoxy)-2-((3,4-dimethoxypyridin-2-
yl)methylsulfinyl)-1H-benzo[d]imidazole
AUTACOIDS
 HISTAMINE

Histamine1-Receptor Antagonists (Classical)

 Histamine1-Receptor Antagonists (Classical)

DIPHENHYDRAMINE CHLORPHENIRAMINE
(Ethanolamine) (Alkylamine)

MEPYRAMINE (PYRILAMINE) HYDROXYZINE

(Ethylenediamine) (Piperazines)
!  DIPHENHYDRAMINE
"  Ethanolamine (amino alkyl ethers)
"  Presence of CHO connecting moeity between
diaryl and amino group
"  SAR:
"  Basic Nitrogen – for binding affinity and

formation of stable solid salts

"  Replacement of one of the phenyl rings with

2-pyridyl group enhances antihistaminic activity

!  PYRILAMINE MALEATE
"  Ethylenediamines derivative
"  Presence of N-connecting atom
"  SAR:
"  Substitution of para methoxy,

chloro or bromo further enhances

activity
!  HYDROXYZINE
"  Cyclizines
"  Connecting moeity CHN group
"  Piperazine moeity
"  Moderately potent antihistamine
"  Slow onset of action
"  Long duration of action
!  CHLORPHENIRAMINE
"  Propylamines
"  With saturated carbon connecting moeity
"  Consist of phenyl and 2 pyridyl aryl group and
terminal dimethyl amino group
"  Differ in phenyl substituents at para position:
H (Pheniramine)
Cl (Chlorpheniramine)
Br (Brompheniramine)
"  For rhinitis and urticaria
!  PHENOTHIAZINES
 Histamine1-Receptor Antagonists
(Non-Sedating)

AZELASTINE LORATADINE

MIZOLASTINE FEXOFENADINE
 Azelastine

!  4-[(4-chlorophenyl)methyl]-2- (1-methylazepan-4-
yl)-phthalazin-1-one
!  rapid onset of action:
!  15 minutes with the nasal spray
!  3 minutes with the eye drops

!  effect lasts for 12 hours

 Loratidine

!  Schering-Plough
!  Brand: Claritin, Claritin-D
 Loratidine

!  Schering-Plough
!  3rd Generation
!  Brand: Claritin, Claritin-D (pseudoephedrine)
!  Claritin-potential side-effects of insomnia, anxiety, and
nervousness
 Loratidine

!  Schering-Plough
!  3rd Generation
!  Brand: Claritin, Claritin-D (pseudoephedrine)
!  Claritin-potential side-effects of insomnia, anxiety, and
nervousness
SAR: Chemically related to TCA (imipramine)
Mizolastine

!  It blocks H1receptors
!  commonly fast-acting
!  does not prevent the actual release of histamine from
mast cells, just prevents it binding to receptors
!  Side effects can include dry mouth and throat
!  2-[{1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-
yl]piperidin-4-yl}(methyl)amino]pyrimidin-4(1H)-
one
SEROTONIN
!  SUMATRIPTAN
"  Serotonin agonist
"  Activates vascular serotonin 5-HT1
receptor
promotes vasoconstriction
"  Tx for migraine and headache
"  it is an analog of the naturally occurring neuro-active alkaloids:
dimethyltryptamine (DMT), bufotenine, and 5-methoxy-
dimethyltryptamine,
"  with an N-methyl sulfonamidomethyl- group at position C-5 on
the indole ring
 SEROTONIN
#  ONDANSETRON

# Antagonist
# Selectively antagonizes 5-HT3 receptor
# For nausea and vomiting
# 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-
1H-carbazol-4(9H)-one
•  first marketed by GlaxoSmithKline as Zofran
 Leukotriene

!  family of eicosanoid
!  inflammatory mediators produced in leukocytes by
the oxidation of arachidonic acid by the enzyme
arachidonate 5-lipoxygenase
!  First discovered in the leukocytes
 LEUKOTRIENE
ANTAGONISTS
1.  Lipoxygenase Inhibitor

- treatment for asthma

N- [1- (1- benzothien-2-yl) ethyl]- ZILEUTON

N- hydroxyurea
 LEUKOTRIENE
ANTAGONISTS
2. Leukotriene Antagonist
MONTELUKAST

- For prophylaxis and chronic

treatment for asthma
- Exercise induced asthma
- Allergic rhinitis

2-(1-((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-
yl)phenyl)propylthio)methyl)cyclopropyl)acetic acid
 PROSTAGLANDINS

•  unsaturated carboxylic acids

•  consisting of of a 20 carbon skeleton
•  contains a five member ring
•  biochemically synthesized from the fatty acid,
arachidonic acid
DRUGS FOR GOUT
DRUGS FOR GOUT

ALLOPURINOL
DRUGS FOR GOUT

COLCHICINE
Cardiovascular Drugs
ANTIANGINAL
DRUGS
 Organic Nitrates

!  Isosorbide dinitrate !  Nitroglycerin

!  Antiangina

Isosorbide dinitrate
1,4:3,6-dianhydro-2,5-di-
O-nitro-D-glucitol
 Calcium Channel Blocker

!  Nifedipine
!  Nitro – anti angina effect

#  SAR:
#  Pyridine ring – partially saturated

#  Position 2 and 6 substituted with

alkyl group
#  Position 3 and 5 carboxylic

#  Position 4 is aromatic with an

electron withdrawing group in an
ortho or meta position (Cl, NO2)
BETA BLOCKERS
ANTIHYPERTENSION
DRUGS
 Renin-Angiotensin Inhibitor

!  Captopril
"  Thiolcontaining ACE
inhibitor.
(Ex. Lisonopril)
 ACE Inhibitor Prodrug

!  Enalapril Maleate
!  For mild to moderate HT

!  Non thiol containing ACE inhibitor

 Angiotensin II Blocker

!  Losartan
!  First non peptide imidazole to be introduced as an orally active
angiotensin II antagonist
 Adrenergic System Inhibitors

!  Reserpine
!  Guanethidine
 Potassium Channel Antagonist

!  Diazoxide
!  analog of benzothiazine diuretics

!  Increase cardiac output

!  IV
!  Minoxidil (triaminotriazine)
!  Vasodilator

!  Increase cutaneous

blood flow
 Minoxidil

!  contains nitric oxide chemical moiety and may act as a

nitric oxide agonist
!  potassium channel opener, causing hyperpolarization
of cell membranes.
!  Minoxidil is less effective when there is a large area of
hair loss
!  Effective for younger men who have experienced hair
loss for less than 5 years.
!  Minoxidil use is indicated for central (vertex) hair loss
only
!  Minoxidil is also a vasodilator by widening blood vessels
and opening potassium channels, it allows more
oxygen, blood, and nutrients to the follicle.
!  cause follicles in the telogen phase to shed, which are
then replaced by thicker hairs in a new anagen phase.
 Positive Inotropic Agents

!  Digitoxin
!  Increase the force

of contraction of the
heart
!  Treatment for CHF
#  increases cardiac muscle contraction
Amrinone Milrinone
Drug for Hyperlipidemia
 Drug for Hyperlipidemia

!  Atorvastatin
!  Lipitor
!  Synthetic lipid lowering
agent
!  Simvastatin (naphthalenyl)
!  The drug is in the form of an inactive lactone that is
hydrolyzed after ingestion to produce the active
agent
!  synthetic derivative of a fermentation product of
Aspergillus terreus
!  Other examples:
!  Lovastatin
!  Fluvastatin

!  Pravastatin
!  Probucol
!  Inhibit synthesis of apoprotein A-1 (major component of HDL)
 Antiobesity

!  Orlistat Orlistat
!  Xenical
!  Lipase inhibitors
!  It works in the intestines,
where it blocks some of the
fat you eat from being
absorbed and digested. This
undigested fat is then
removed in your bowel
movements (BM).
ORAL HYPOGLYCEMIC
DRUGS
 SULFONYLUREAS

!  Stimulate release of insulin

from pancreatic B cells Chlorpropamine

!  1st and 2nd generation

!  Urea derivatives w/ aryl

sulfonyl group at 1 position
and aliphatic group at 3
position

!  Chlorpropamide,Tolbutamide
(1st generation)
!  Acidic compound

Tolbutamide (ist generation)

!  2nd Generation
Cyclohexylsulfonylurea
2nd generation

Glipizide (pyrazine ring)

!  2nd Generation
!  Glimeperide (pyrrolidine ring)
!  2nd Generation
!  Gliclazide
"  Pyrrolidine increases lipophilicity of tolbutamide
Nonsulfonylureas - METAGLINIDES

!  Repaglinide (piperidinyl chain)

!  Fast onset but short duration of action
 THIAZOLINEDIONES

!  Pioglitazone
!  Normalize glucose metabolism

!  Reduce the amount of insulin needed to achieve glycemic

control
 BIGUANIDES

!  Metformin
!  Reduce sugar absorption in the GIT

!  Unable to stimulate release of insulin from pancreas

!  Antihyperglycemic agent
 ALPHA GLUCOSIDASE INHIBITOR

!  Acarbose
!  Reduce absorption of starch, dextrin and disaccharides
 THYROID HORMONES

!  Levothyroxine Sodium
!  Replacement therapy of decrease thyroid function
 ANTITHYROID DRUGS

!  Thiourea !  Thiouracil
 DIURETIC DRUGS

!  Structure contains the sulfamoyl group – NH2SO2

!  The sulfamoyl group should be unsubstituted to
retain activities. It is attached to an aromatic
character
 DIURETICS

!  Osmotic Diuretics
!  Mannitol, Urea, glycerin
!  Highly polar,water soluble

Mannitol
!  Carbonic Anhydrase
Inhibitors
!  Aromatic or heterocyclic
sulfonamides with a
prominent thiadiazole
nucleus
!  Unsubstituted sulfamoyl
(#5 of 1,3,4 Thiadiazole)
!  Benzothiadiazide
!  Thiazide ; #7 sulfamoyl; #6 activating group (Cl,Br) is
essential for diuretic activity
!  Chlorothiadiazide

Thiazide

4
 High Ceiling or Loop Diuretic

!  Furosemide
!  5 sulfamoyl 2 and 3
aminobenzoic acid
!  Carboxyl group provides
optimal diuretic activity
!  Activating group in the 4
position like Cl and CF3
!  Sulfamoyl group in the 5
position for high ceiling
diuretic activity

Furosemide
!  Potassium Sparing
Diuretic
!  Steroidal
!  Aldosterone antagonist

Spironolactone
 Hormones

!  Secreted by endocrine gland

!  Proteins or steroids
!  Cyclopentanoperhydrophenanthrene
!  Water insoluble
 Adrenal Cortex Hormone

!  Aldosterone
!  Primary
mineralocorticoid in
humans
!  Cause significant salt
retention
 Hydrocortisone

!  Primary glucocorticoid in
human
!  Glucorticoids with
moderate to low salt
retention
!  Cortisone,hydrocortisone
,prednisone
!  antiinflammatory

Hydrocor'sone+
 Beclomethasone

!  Glucocorticoid with very

little or no salt retention
!  antiinflammatory

Beclomethasone+
dipropionate+
 Parathyroid Hormones
!  Linera polypeptide containing
84 amino acid residues
!  Dihydrotachysterol had been
used in lieu of parathyroid
hormone in the Tx of
hypocalcemia and
hypoparathyroidism

Dihydrotachysterol%
 Thyroid Hormones

!  Hypothyroidism
!  Thyroglobulin content
(iodine containing
globulin)

Levothyroxine%Na%
 Antithyroid Drugs

!  Hyperthyroidism !  Thiourea
!  Cabbage- antithyroid;
ionic inhibitors;thyroid
inhibitors; produce
thiocyanate
!  Thiourylenes

PTU%

Methimazole%
 Sex Hormones

!  Estrogenic Hormone
!  Methyl group at C18,
aromatic ring
!  Oral contraceptive with
progestins,osteoporosis,
menopausal symptoms

Estradiol+
 Synthetic Estrogens

!  Nonsteroidal stilbene
derivatives
!  Estradiol like
conformation in vivo
!  Diethylstilbestrol (DES)
 DES Analog

Chlorotrianisene%
 Antiestrogen

!  Estrogen antagonist
!  Ovulation stimulant (Clomiphene)
!  Structurally similar to Chlorotrianisene
!  Tamoxifen(estrogen dependent breast cancer
Tamoxifen+ Clomiphene+
 Progestins

!  Progesterone
!  Medroxyprogesterone
!  Progesterone
(suppository)
!  Birth control,reduce risk
of endometrial
cancer,secondary
amenorrhea
!  Acetyloxy group at C17
incraese lipid solubility
and decrease first pass
metabolim
!  Enhance oral activity
 Testicular Hormone

!  Testosterone(androgenic
; anabolic)
Androstane
!  Androgenic hormones
!  Male sex promoting;
anabolic agents; muscle
building

Testosterone+
 Androgen antagonist

!  Antiandrogen
!  Hyperandrogenism(hirsu
tism, premature baldness