TARGETS FOR DEVELOPMENT OF ANTI-ULCER AGENTS

By
Vamsi rajasekhara reddy

M-Pharmacy 1st Year (Pharmaceutical Chemistry)

CONTENT
FACTORS FOR ULCERATION PHYSIOLOGY OF ACID SECRETION TARGETS OF ANTIULCER AGENTS MECHANISM OF ACTION SIDE EFFECTS

PATHOGENIC FACTORS FOR ULCERATION

Imbalance between the aggressive and the defensive factors. Acid secreted by parietal cells is aggressive factor. Gastric mucosa, bicarbonate secretion, prostaglandins nitric oxide are defensive factors Helicobacter pylori infection.

ACID SECRETION BY STOMACH

Gastric acid secreted by parietal cells. Basolateral membrane of these cells contain 3 main stimulants Gastrin (from G cells) Histamine (from enterochromaffin cells) Acetylcholine (from vagal efferent) These stimulants stimulate proton pump Stimulated proton pump translocates from cytoplasmic vesicles to the secretory canaliculus of the parietal cells + Uses energy derived from hydrolysis of ATP, to transport H out of parietal + cells in exchange for K Hydrogen ions combine with Chloride ions to form hydrochloric acid(HCl) Hydrochloric acid is secreted in to gastric lumen.

Secretion of acid by parietal cells

TARGETS
H2 receptor eg: Cimetidine, Ranitidine, Famotidine Proton Pump eg: Omeprazole, Lansoprazole, Pantoprazole M1 receptor eg: Pirenzipine, propantheline, Oxyphenonium Gastrin receptors eg:Misoprostol, Enprostil, Rioprostil Cell wall eg:sucralfate Stomach eg: Antacids ( sodium bicarbonate, Magnesium hydroxide ) Helicobacter pylori eg:Amoxycillin, Clarithromycin, Metronidazole

H2 RECEPTOR

ranitidine

cimetidine

SAR

Imidazole ring exist in two tautomeric forms. In these form I to be necessary for maximal H2 antagonist activity. When R is substituted with methyl group, the activity is potentiated The other heterocyclics like furan, thiazole enhance the potency and selectivity of H2 receptor antagonism

The ring and terminal nitrogen should be separated by four carbon atom for optimum activity. The shorter chain decrease the activity. The side chain should contain an electron with drawing substituents and an Isosteric thioether (- S-) link in place of methylene group (- CH2) leads to more active compound. The terminal nitrogen should be polar, non basic substituents for maximal activity.

Synthesis of Cimetidine

Histamine H2 Receptor Antagonist

 Reversible competitive inhibitors of H2 receptor  Highly selective, No action on H1 or H3 receptors  Very effective in inhibiting nocturnal acid secretion ( as it

depends largely on Histamine )

 Modest impact on meal stimulated acid secretion (As it

depends on gastrin, acetyl choline and histamine)

H2 BlockersSide effects & Interactions

 Extremely safe drugs  Mental status changes may occur  Cimetidine inhibits metabolism of estradiol and

increase prolactin level

 Cimetidine increases concentration of Warfarin,

Theophylline, Phenytoin, Ethanol.

PROTON PUMP

Examples

HOH2C

N SOCl2

ClH2C

H3C OCH3

CH3

H3C

CH3 NaOH

OCH3 2 chloromethyl 3,5 dimethyl 4 methoxy pyridine

KS
N NH2

S H3CO

SH

H3CO

NH2

N H potassium ethyl H5C2O xanthate 5 methoxy 2 mercaptobenzimidazole O N OH H3CO Cl O N NH S CH2 CH3 OCH3 N CH3 N H S H3C OCH3 CH2 N CH3

4 methoxy O phenylene diamine

H3CO

Omeprazole

Proton Pump Inhibitors

 Most effective drugs in antiulcer therapy  Irreversible inhibitor of H+ K+ ATPase  Prodrugs requiring activation in acid environment  Weakly basic drugs & so accumulate in canaliculi of parietal

cell
 Activated in canaliculi & binds covalently to extracellular

domain of H+ K+ ATPase

 Acid secretion resumes only after synthesis of new molecules

Poton Pump Inhibitors Kinetics

 Given as enteric coated granules in capsule or enteric

coated tablets
 Pantoprazole also given intravenously  Half life 1.5 hrs  Since it requires acid for activation - given 1 hr

before meals Other acid suppressing agents not coadministered

P.P.I. Side effects & Interactions

 Extremely safe drugs  Causes hypergastrinemia which leads to carcinod

tumor in rats
 But no evidence of such tumors in man  Inhibit CYP 450 & hence metabolsim of warfarin,

phenytoin, etc
 Pantoprazole & Rabeprazole have no significant

interactions

M1 RECEPTORS

O NH2 Cl O 2N 2 Nitrobenzoyl chloride

Cl O

+
N 3 Amino
-

NH

-H C l
O 2N

Cl

Chloropyridine H2 Raney Ni

H N

Cl O

2 0 0 C
NH N H

-H C l
O H 2N
2 Cl

ClCOCH

N(CH 3 ) 3 H N HN N CH3

H N

N O O

N O ClH 2 C O

-HCl

N H 3C

M1 RECEPTOR ANTAGONIST

Block M1 receptor at enterochromaffin cells Donot cross Blood Brain Barrier Nonselective Blurred vision, dry mouth, urinary retention Delay gastric emptying Eg: Propantheline, Oxyphenonium, Pirenzepine, Telenzepine

GASTRIN RECEPTORS

PROSTAGLANDIN ANALOGUES
Produced in gastric mucosa Inhibits gastrin release Enhances mucosal blood flow Stimulates secretion of mucus and bicarbonates NSAID associated gastrointestinal injury Need multiple daily dosing Diarrhoea, abdominal cramps, uterine contractions Eg: Misoprostol, Enprostil Rioprostil

CELL WALL

Mucosal Protective Agents

 Sucralfate  Colloidal Bismuth compounds

Sucralfate

 In acidic pH polymerises to viscous gel that

adheres to ulcer crater

 Taken on empty stomach 1 hr. before meals  Salt of sucrose complexed to sulfated aluminium

hydroxide
 Concurrent antacids, H2 antagonist avoided

( as it needs acid for activation )

Colloidal Bismuth Compounds

 Coats ulcer, stimulates mucus & bicarbonate secretion  Direct antimicrobial activity against H.pylori  May cause blackening of stools & tongue  Not used for long periods bismuth toxicity

Available compounds :
Bismuth subsalicylate in USA Bismuth subcitrate in Europe Bismuth dinitrate

STOMACH

ANTACIDS

 Weak bases that neutralize acid  Also inhibit formation of pepsin

(As pepsinogen converted to pepsin at acidic pH)

 Present day antacids :

Aluminium Hydroxide Magnesium Hydroxide

Duration of action :
 30 min when taken in empty stomach  2 hrs when taken after a meal

Side effects :
 Al3+ antacids constipation (As they relax gastric

smooth muscle & delay gastric emptying)

 Mg2+ antacids Osmotic diarrhoea .  In renal failure Al3+ antacid Aluminium toxicity

Antacid Interactions
Adsorb drugs and form insoluble complexes that are not absorbed

HELICOBACTER PYLORI

Eradication of H.pylori
Triple Therapy The BEST among all the Triple therapy regimen is Omeprazole / Lansoprazole Clarithromycin Amoxycillin / Metronidazole - 20 / 30 mg - 500 mg - 1gm / 500 mg

 Given for 14 days followed by P.P.I for 4 6 weeks  Short regimens for 7 10 days not very effective

Some other Triple Therapy Regimens are

 Bismuth subsalicylate

- 2 tab - 250 mg - 500 mg - 400 mg - 500 mg

Metronidazole Tetracycline

 Ranitidine Bismuth citrate

Tetracycline

Clarithromycin / Metronidazole - 500 mg

Quadruple Therapy
 Given when Triple Therapy fails  Omeprazole / Lansoprazole - 20 / 30

Bismuth subsalycilate Metronidazole Tetracycline

- 2 tabs - 250 - 500

FUTURE PROSPECTS
Reversible proton pump inhibitors are currently underdevelopment by the company Astra-Zeneca. Development of vaccine for Helicobacter pylori is currently being explored.

REFERENCE:
FOYES PRINCIPLES OF MEDICINAL CHEMISTRY 1019-1024 Essentials of MEDICAL PHARMACOLOGY K D Tripathi 587-598 Clinical Pharmacology by P N Bennett M J Brown 561-568 An Introduction to Medicinal Chemistry by Graham L. Patrick 642-670 Principles of Pharmacology by H L Sharma K K Sharma 386-399 http://aac.asm.org/cgi/content/full/48/12/4582?maxtoshow=&HITS=10 &hits=10&RESULTFORMAT=&fulltext=cimetidine+synthesis&searchid=1&FI RSTINDEX=0&resourcetype=HWCIT http://aac.asm.org/cgi/content/full/51/3/831 http://jac.oxfordjournals.org/cgii/content/full/59/1/160

THANK YOU