H1 and h2 receptor antagonist

H1 and h2 receptor antagonist , their distribution, uses, SAR , Ppis (proton pump inhibitors)

1. H 1 AND H 2 RECEPTOR ANTAGONIST Presented by: Shubham Sharma Pharmaceutical Chemistry Roll no. : 20029 Presented to : Dr. Ranju Bansal Professor ,UIPS, Panjab University SEMINAR ON

2. 2/5/2021 UIPS, PANJAB UNIVERSITY 2 CONTENTS INTRODUCTION , SYNTHESIS AND MOA OF HISTAMINE CLASISIFICATION OF H 1 ANTIHISTAMINES SAR OF H 1 ANTIHISTAMINES SYNTHESIS INTRODUCTION AND MOA OF H 2 ANTIHISATMINES SAR , CLINICAL USES AND SYNTHESIS OF H 2 ANTIHISTAMINES INTRODUCTION, MOA , CINICAL USES AND SAR OF PPI’S

3. Histamine is an organic nitrogenous compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter for the brain, spinal cord and uterus. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. HISTAMINE 2/5/2021 UIPS, PANJAB UNIVERSITY 3

4. 2/5/2021 UIPS, PANJAB UNIVERSITY 4 SYNTHESIS AND METABOLISM Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine. Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyl transferase or diamine oxidase . In the central nervous system, histamine released into the synapses is primarily broken down by histamine-N-methyl transferase, while in other tissues both enzymes may play a role.

5. 2/5/2021 UIPS, PANJAB UNIVERSITY 5 Continued….

6. 2/5/2021 UIPS, PANJAB UNIVERSITY 6 HISTAMINE RECEPTORS AND ITS MECHANISM OF ACTION

7. 2/5/2021 UIPS, PANJAB UNIVERSITY 7 H 1 -ANTIHISTAMINES H 1 -antihistamines are not receptor antagonist, but are inverse agonist in that they produce the opposite effect on the receptor to histamine. Consequently, the preferred term to define these drugs is “H 1 antihistamines” rather than “H 1 antagonist”. Clinical Uses of Antihistamines Allergic rhinitis (common cold) Urticaria (hives) Pruritus (atopic dermatitis, insect bites) Anaphylactic reactions (severe allergies) Nausea and vomiting (first generation H1- antihistamines ) As anti-tussives Eg : diphenhydramine. As anti-emetic Eg: meclizine. In “parkinsonism ” Eg: promethazine , diphenhydramine. In drug induced “acute dystonias” Eg: diphenhydramine, promethazine. To treat “motion & morning sickness” Eg: cyclizine, promethazine. To treat “vertigo” conditions Eg: cinnarizine.

8. 2/5/2021 UIPS, PANJAB UNIVERSITY 8 ADVERSE EFFECTS Associated with the first generation H1-antihistamines and due to their lack of selectivity for the H1 receptor and anti-cholinergic activity. Side effects are due to CNS depression: Sedation Dizziness Tinnitus (ringing in the ear) Blurred vision Euphoria Anxiety Insomnia Dry mouth/dry cough Newer second generation H1-antihistamines are more selective for the peripheral histamine receptors and have far less side effects (drowsiness, fatigue, headache, nausea and dry mouth) .

9. 2/5/2021 UIPS, PANJAB UNIVERSITY 9 Development of antihistamines began by the discovery of piperoxam. The drugs shown below will inhibit the action of released histamine :

10. 2/5/2021 UIPS, PANJAB UNIVERSITY 10 Note ; this structure resembles with structure of anticholinergics drugs.

11. 2/5/2021 UIPS, PANJAB UNIVERSITY 11 AMINOALKYL ETHERS (ETHANOLAMINES) Diphenylpyraline Piperidine is introduced

12. 2/5/2021 UIPS, PANJAB UNIVERSITY 12 Pyrrolidine is introduced

13. 2/5/2021 UIPS, PANJAB UNIVERSITY 13 These are characterized by presence of oxygen connecting moiety . Most compounds in this series are simple N,N-dimethyl ethanolamine derivatives. Clemastine differs from basic structural pattern . Most amino alkyl ethers are optically active . Replacement of one of the phenyl rings of the diphenydramine with a 2-pyridyl group as in doxylamine will enhance antihistaminic activity. This amino alkyl ethers have to penetrate the BBB and occupy central H1 receptor resulting the drowsiness . Conversion to a quaternary ammonium salt does not alter the antihistaminic activity but does increases in anticholinergic action . STRUCTURE ACTIVITY RELATIONSHIP

14. 2/5/2021 UIPS, PANJAB UNIVERSITY 14 ETHYLENE DIAMINE DERIVATIVES 2-pyridyl group is introduced 2-thienyl methyl group is introduced Pyrimidine is introduced

15. 2/5/2021 UIPS, PANJAB UNIVERSITY 15 STRUCTURE ACTIVITY RELATIONSHIP These are characterized by nitrogen connecting atom . R1 and R2 should be small (CH3) for maximum H1-antagonist activity . Ar1 and Ar2 can be benzene ring or any other isosteric rings such as heterocycles . One of the aromatic should be benzyl for better activity which has P- substitution . Phenbenzamine was first clinically useful member . Replacement of phenyl moiety of Phenbenzamine with a 2-pyridyl system yielded “ tripelennamine ” . Replacement of benzyl group of tripelennamine with a 2-thienylmethyl group provided “methapyriline” . Replacement of tripelennamine with 2-pyridyl group with a pyrimidinyl moiety yields “thonzylamine”. The anticholinergic & antiemetic action of these compounds are low.

16. 2/5/2021 UIPS, PANJAB UNIVERSITY 16 PROPYL AMINE DERIVATIVES

17. 2/5/2021 UIPS, PANJAB UNIVERSITY 17 STRUCTURE ACTIVITY RELATIONSHIP Phenyl substituent at P-position replaces with “Cl” is chlorpheniramine & “Br” is bromopheniramine . These halogenated pheniramines are more potent & have a longer duration of action . The agents in this class produce less sedation than the other classical antihistamines.

18. 2/5/2021 UIPS, PANJAB UNIVERSITY 18 CONTINUED…

19. 2/5/2021 UIPS, PANJAB UNIVERSITY 19 PIPERAZINE DERIVATIVES

20. 2/5/2021 UIPS, PANJAB UNIVERSITY 20 Note : Cetrizine belongs to second generation h 1 antihistamines

21. 2/5/2021 UIPS, PANJAB UNIVERSITY 21 STRUCTURE ACTIVITY RELATIONSHIP These are ethylene diamine derivatives. Connecting moiety(X) is CHN group . These are moderately potent, with low incidence of drowsiness, slow onset of action & exhibit peripheral & central antimuscarnic activity. Primary structural difference is nature of Para aromatic ring substituent.

22. 2/5/2021 UIPS, PANJAB UNIVERSITY 22 PHENOTHIAZINE DERIVATIVE

23. 2/5/2021 UIPS, PANJAB UNIVERSITY 23 STRUCTURE ACTIVITY RELATIONSHIP Phenothiazine derivatives that contain a 2/3 carbon branched alkyl chain between alkyl chain between the ring system and terminal nitrogen atom . This differs the phenothiazine’s from antipsychotic series in which an unbranched propyl chain is required . P romethazine , the parent member of this series is moderately potent & with prolonged action & pronounced sedative side effects . The combination of lengthening of side chain & substitution of lipophilic groups in 2nd position of aromatic ring results in compounds with decreased antihistaminic activity & increased psychotherapeutic properties. METABOLISM : These compounds undergo mono-di & N- dealkylation , sulfur oxidation, aromatic oxidation at 3rd position to yield phenol & N-oxidation.

24. 2/5/2021 UIPS, PANJAB UNIVERSITY 24 PIPERIDINE DERIVATIVES NOTE: Cyproheptadine and azatidine can also be kept under heptanes . Loratidine belongs to 2 generation h 1 antihistamines.

25. 2/5/2021 UIPS, PANJAB UNIVERSITY 25 These are the phenothiazine analogues in which sulfur atom is replaced by an isosteric vinyl group (cyproheptadine) or saturated ethyl bridge (AZATIDINE ). Other second generation H 1 antihistamines Note : Cetrizine and Loratidine already has been covered earlier.

26. 2/5/2021 UIPS, PANJAB UNIVERSITY 26 CONTINUED… Terfenadine is a long acting h 1 antagonist. Fexofenadine is a primary oxidative metabolite of terfenadine and do not cross BBB. Desloratidine is an active metabolite of loratidine. Drugs which will inhibit the release of histamine

27. 2/5/2021 UIPS, PANJAB UNIVERSITY 27 These drugs act by stabilizing the mast cells & inhibit the release of histamine & other mediators of inflammation . Natural product khellin led to the development of bis compounds . C romolyn nasal solution used for the prevention & treatment of allergic rhinitis . Oral concentrate used to treat the histaminic symptoms of mastocytosis. CONTINUED…

28. 2/5/2021 UIPS, PANJAB UNIVERSITY 28 PROMETHAZINE SYNTHESIS

29. 2/5/2021 UIPS, PANJAB UNIVERSITY 29 DIPHENYDRAMINE SYNTHESIS

30. 2/5/2021 UIPS, PANJAB UNIVERSITY 30 H 2 RECEPTOR AND ITS MECHANISM OF ACTION H 2 receptors are mainly present in the stomach over the parietal cells which is responsible for binding with the histamine and thus induce acid release while other receptors present over there will just enhance its action and have a very little role in acid secretion.

31. 2/5/2021 UIPS, PANJAB UNIVERSITY 31 H 2 RECEPTOR ANTAGONIST H 2 antagonist are competitive antagonist of histamine

32. 2/5/2021 UIPS, PANJAB UNIVERSITY 32 H 2 ANTAGONIST IMIDAZOLE RING THIAZOLE RING

33. 2/5/2021 UIPS, PANJAB UNIVERSITY 33 FURAN RING THIAZOLE RING

34. 2/5/2021 UIPS, PANJAB UNIVERSITY 34 STRUCTURE ACTIVITY RELATIONSHIP

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37. 2/5/2021 UIPS, PANJAB UNIVERSITY 37 RANITIDINE SYNTHESIS

38. 2/5/2021 UIPS, PANJAB UNIVERSITY 38 CLINICAL USES:

39. 2/5/2021 UIPS, PANJAB UNIVERSITY 39 PROTON PUMP INHIBITORS They are prodrugs that activate in acid environment. After absorption, the active metabolite diffuses into the parietal cells and accumulates in the acidic secretory canaliculi. The consumption of food stimulates acid secretion and acid secretion activates PPIs. Then activated PPI is converted to a sulfenamide in the acidic secretory canaliculi of the parietal cell. The sulfenamide interacts covalently with sulfhydryl groups in the proton pump and make complex, thereby irreversibly inhibiting its activity. Proton Pump Inhibitor Blocking the H+/K ATPase

40. 2/5/2021 UIPS, PANJAB UNIVERSITY 40 CONSIDER IT AS OMEPRAZOLE

41. 2/5/2021 UIPS, PANJAB UNIVERSITY 41 Dyspepsia Peptic ulcer Gastro esophageal reflux disease (GERD ) Laryngopharyngeal reflux Stress gastritis prevention Zollinger-Ellison syndrome Proton Pump Inhibitor Medical Uses

42. 2/5/2021 UIPS, PANJAB UNIVERSITY 42 The Substituted pyridine ring, substituted benzimidazole moiety & methyl sulfinyl chain connecting these two is essential for the biological effect. Biological activity & chemical stability largely depends on their substitution pattern. Pyridine substitution compared to timoprazole 4-methoxy group in the pyridine ring increases the biological activity by enhancing nucleophilicity of pyridine nitrogen atom . A 4-fluro alkoxy substitution combining lipophilicity & electron demanding properties results strong inhibitory activity. Eg: Lansoprazole SAVIPRAZOLE Benzimidazole substitution by electron demanding group leads to strong activity . Benzimidazole substitution by electron accepting group leads to less activity. STRUCTURE ACTIVITY RELATIONSHIP

43. UIPS, PANJAB UNIVERSITY 43 1. TIMOPRAZOLE Discovered in 1975 2. OMEPRAZOLE A derivative of timoprazole, omeprazole, was discovered in 1979, and was the first of a new class of drug that control acid secretion in the stomach, a proton pump inhibitor (PPI). Addition of 5-methoxy- substitution to the benzimidazole moiety of omeprazole was also made and gave the compound much more stability at neutral pH. 3. LANSOPRAZOLE Lansoprazole was the second of the PPI drugs to reach the market, being launched in Europe in 1991 and the US in 1995. It has no substitutions at the benzimidazole but two substituents on the pyridine: M ethyl group at position 3. Trifluoroethoxy group at position 4. The drug is a 1:1 racemate of the enantiomers dexlansoprazole and levolansoprazole .

44. 2/5/2021 UIPS, PANJAB UNIVERSITY 44 Pantoprazole was the third PPI and was introduced to the German market in 1994. It has a difluoroalkoxy sidegroup on the benzimidazole part and two methoxy groups in position 3 and 4 on the pyridine. Pantoprazole was first prepared in April 1985 by a small group of scale-up chemist. 4. PANTOPRAZOLE 5. RABEPRAZOLE It is similar to lansoprazole in having no substituents on its benzimidazole part and a methyl group at site 3 on the pyridine, the only difference is the : Methopropoxy substitution at position 4 intstead of triflouroethoxy group on lansoprazole

45. 2/5/2021 UIPS, PANJAB UNIVERSITY 45 6. ESMOPRAZOLE Esomeprazole magnesium (Nexium) received its first approval in 2000 and provided more pronounced inhibition of acid secretion and less inter-patient variation compared to omeprazole. 7. DEXLANSOPRAZOLE Dexlansoprazole was launched as a follow up of lansoprazole in 2009. dexlansoprazole is an R- enantiomer of lansoprazole, marketed as Dexilant. After oral appliance of the racemic lansoprazole, the circulating drug is 80% dexlansoprazole . Moreover, both enantiomers have similar effects on the proton pump

46. 2/5/2021 UIPS, PANJAB UNIVERSITY 46 REFERENCES JOHN H.BLOCK & JOHN M. WILSON& GISVOLD’S - Organic Medicinal & Pharmaceutical chemistry. (Pg.): 698 – 728. D.SRIRAM & P.YOGEESWARI -Medicinal chemistry. (Pg.): 278 – 302 . BERTRAM G.KATZUNG, SUSAN B.MARTERS ANTHONY J.TREVOR - Basic & Clinical pharmacology (Pg.) : 277 . K.D TRIPATHI Essentials of Medical pharmacology. (Pg.): 159 – 160. FOYE’S Principles of Medicinal chemistry. (Pg.): 1045.

47. 2/5/2021 UIPS, PANJAB UNIVERSITY 47 THANK YOU