Anti histamines drugs

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1. Anti Histamines D rugs Ravish Yadav

2. What are histamines? Important chemical messenger, communicating information form one cell to another Involved in variety of biological actions Stored in inactive form and released as a result of an antigen antibody reaction initiated by different stimuli. At physiological pH  monocationic conjugate species  Structure of histamine and nomenclature 4(5-)(2-aminoethyl)imidazole 80% N Ʈ In aqueous solution 20% N ∏ 2 4:2 Ratio of existence Tautomers

3. 3 DICATIONIC SPECIES At physiological pH  monocationic conjugate species

4. Stereochemistry : Achiral, trans and gauche rotamers 4 Trans  H1 & H2 agonistic Gauche  H1 agonistic

5. Pharmacology of Histamine : Biosynthesis and Storage Histidine decarboxylase in presence of pyridoxyl phosphate In human : CSF, skin, bronchial and intestinal mucosa Storage and release : in mast cells and basophills . Released by exocytosis as a response to immune (Ag-Ab) and non-immune (Drug , phy . factors) stimuli. RECEPTORS : G - protein coupled receptors. H1  Allergy H2  Gastric acid secretion H3 Neurotransmitter in CNS 5 Histamine S- Histidine

6. Metabolism : by enzyme inactivation 6 Conjugation as ribosyl residue N Ʈ -Me-histamine SAM SAH (BRAIN) DAO/MAO (Oxidative Deamination) N-Me-imidazole acetic acid HMT : Histamine N-Me- transferase SAM : S- adenosyl –L-methionine SAH : S- adenosyl –L- homocysteine

7. Histamine receptors and its function: 4 different types of receptors (G-protein coupled) H1 : found in mammalian brain , smooth muscle from airways, GI tract, genitourinary system, CVS, adrenal medulla & endothelial cells & lymphocytes. Histamine which act on H1 receptors causes inflammation Anti- histamines, which act on this receptor are used as anti-allergy drugs Molecular mass of this receptor is 56 kd & represents 487 amino acids Receptor contains 7 hydrophobic trans-membrane domains (TM) TM-3 & TM-5 are main sites for binding of H1-receptor ligands. 7

8. H2 : found in gastric parietal cells, vascular smooth muscles, CNS, Neutrophils , Heart, Uterus function : stimulation gastric acid secretion , regulates gastrointestinal motility &intestinal secreation . Molecular mass is 40 kd and has about 359 amino acids. Effects of H2 receptor ligand is mediated by a stimulatory G α s protein coupled receptor, which in turn activates adenylate cyclase promoting the synthesis of cAMP . 8

9. H3 : found in CNS, PNS, Heart, lungs, GIT, endothelial cells function :It is coupled to a G i /o protein, which inhibits the action of adenylate cyclase and regulates MAP kinase and intracellular calcium levels. H4 : highly expressed in bone marrow & WBC’s & regulates neutrophil release form bone marrow Also expressed in small intestine, spleen, colon, liver, lungs, tonsils These receptor subtypes may also be involved in allergic inflammatory responses. 9

10. H1 Antagonist MOA of H1 antagonist : Competitively inhibit the action of histamine on tissue containing H1 receptors 1 st Generation or classical antihistamines 2 nd Generation antihistamines : Non-sedating, antagonistic activity at other neurotransmitter receptors like muscarinic receptors and cardiac ion channels. 10

11. 1 st generation : SAR : Diaryl substitution is essential for significant H1 receptor affinity Presence of two aryl rings and substituted amino moieties increases the lipophilicity of the molecule than the endogenous agonist, Histamine. 2 aryl groups must be non-coplanar (not be in same plane) for effective receptor interaction Basic amino group is necessary for attachment of an anionic site of the H1 receptor (N may be a simple dimethyl amino group or a part of heterocyclic ring) Carbon chain consists of usually 2 or 3 atoms . As a result distance between diaryl & terminal N becomes 5 to 6 which is ideal for optimum activity X connecting moiety may be saturated C-O or simply C atom . This group along with C chain, appears to serve as a spacer group for the key pharmacophoric moieties 11

12. 1 st generation antihistamines are further classified into 5 types depending upon connecting moiety and the nature of the aryl moieties: Aminoalkyl ethers ( Ethanolamines ) Ethylenediamines Piperazines ( cyclizines ) Propylamines Tricyclic ring systems (Phenothiazine and heptanes ) 12

13. 1 st generation 1. Aminoalkyl ethers ( Ethanolamines ) Ar Ar 1 R 1. Diphenhydramine Ph Ph H (Benadryl) 2 . Doxylamine Ph CH3 13 S-form is ACTIVE Assymmetric Increased activity

14. 2. Ethylenediamines Ar Ar 1 1. Pyrilamine 2. Tripelennamine 14

15. 3. Piperazines ( cyclizines ) R1 R2 1. Cyclizines H CH3 2. Chlorcyclizine Cl CH3 3. Buclizine Cl 15

16. 4. Propylamines Ar1 Ar 1. Pheniramine 2. Chorpheniramine 3. Bromopheniramine 16 sp2 / sp3

17. 5 . Tricyclic ring systems - Phenothiazines R 1.Promethazine 2.Trimeprazine 17 Unsubstituted heterocyclic ring

18. 6. Tricyclic ring systems – Dibenzocycloheptanes / Heptanes 1. Cyproheptadiene (X=C) 2. Azatidine maleate (X=N) 18 Bioisosterism sp2 - C

19. 2 nd Generation 1) Fexofenidine 4-[1-Hydroxy-4-[4-( hydroxyldiphenylmethyl )-1-piperinyl] butyl-α, α - dimethyl benzeneacetic acid 19

20. Fexofenidine is a primary oxidative metabolite of terfenadine Terfenadine is selective, long acting (>12hr) H1 antagonist with little affinity for muscarinic , serotonergic or adrenergic receptors The histamine receptor affinity of this compound is believed to be related primarily to the presence of diphenylmethyl piperidine moiety Terfenadine undergoes significant 1 st pass metabolism, with the predominant metabolite being fexofenidine , an active metabolite resulting from methyl group oxidation When drug that inhibit this transformation such as imidazole antifungals or macrolides , are used concurrently , terfenadine level may rise to toxic level, resulting in potential fatal heart rhythm problems Fexofenidine , like terfenadine is a selective peripheral H1 receptor ligand that produces no clinically significant anticholinergic effect at therapeutic doses Fexofenadine is rapidly absorbed after oral administration Fexofenidine is 60-70% plasma protein bound & elimination half life is about 14 hrs 20

21. 2) Loratadine 4-(8-Chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta [1,2-b]pyridin-11-ylidene)-1-carboxylic acid ethyl ester 21

22. Related to tricyclic antidepressants, antihistamines azatadine and cyproheptadine & is non sedating & neither it or nor its major metabolite, desloratidine , is associated with potential cardiotoxic effects as that of terfenadine & astemizole Desloratidine is more potent H1 antagonist & more potent inhibitor of histamine release The metabolic conversion of loratidine to descarboethoxyloratidine occurs via a oxidative process & not via direct hydrolysis Both CYP2D6 & CYP3A4 appear to catalyzing this oxidative metabolic process Metabolite is excreted renally as a conjugate & elimination half life is about 8 to 15 hrs 22

23. Metabolism of loratidine 23

24. 3)Cetirizine [2-[4-[(4-chlorophenyl) phenylmethyl ]-1-piperazinyl] ethoxy ] acetic acid 24

25. Cetirizine is primary acid metabolite of hydroxyzine , resulting from complete oxidation of primary alcohol moiety This compound is relatively polar & zwitterionic & thus does not penetrate the BBB readily Has long duration of action & is highly selective for H1 receptor Advantages: rapid onset of activity, once-daily dosing, minimal CNS toxicity & lack of clinical significant effect on cardiac rhythm when administered with imidazole antifungals & macrolide antibiotics Side effects: fatigue, dry mouth, dizziness Since the drug is primarily eliminated by a renal route, its adverse reaction may be more pronounced in individuals suffering from renal insufficiency Cetirizine is indicated for the temporary relief of runny nose , sneezing, itching of nose or throat, etc. Terminal half life is 8.3 hrs 25

26. Levocetirizine Levocetirizine  (as levocetirizine dihydrochloride ) is a third-generation non-sedative antihistamine, developed from the second-generation antihistamine cetirizine. Chemically, levocetirizine is the active enantiomer of cetirizine. It is the  R -enantiomer of the cetirizine  racemate . Levocetirizine is called a non-sedating antihistamine as it does not enter the brain in significant amounts, and is therefore unlikely to cause drowsiness. Latest research shows levocetirizine reduces asthma attacks by 70% in children 26

27. 4) (E,E)-3-[6-[1-(4-methylphenyl)-3- (1-pyrrolidinyl) -1-propenyl-2-pyridinyl]-2-propenoic acid Acrivastine is an analogue of triprolidine containing a carboxyethenyl moiety at the 6 position of pyridyl ring Acrivastine shows antihistaminic potency and duration of action comparable to those of tripolidine Enhanced polarity of this compound resulting from carboxyethenyl substitution limits BBB penetration & thus producing less sedation than tripolidine Half life is 1.7 hr of orally administered drug 27 Triprolidine

28. 5) Astemizole 1-[(4-flurophenyl)methyl]-N- [1-[2-(4-methoxyphenyl)ethyl] -4-piperidyl]benzoimidazol-2-amine One of the limitation of astemizole is that, it produce life threatening arrhythmias when used concurrently with drugs that inhibit their metabolism (like imidazole antifungals & macrolides ) Slow onset of action & long duration It is metabolized slowly & extensively, mainly by aromatic hydroxylation (CYP3A4) Desmethyl metabolite is pharmacology active & hence it could be the reason of extended duration of antihistamine action 28

29. Metabolism of astemizole Desmethyl (active) Aromatic hydroxylation 29

30. 6) Mizolastine 2-[{1-[1-(4-flurobenzyl) -1H-benzimidazol-2-yl]piperidin-4-yl} (methyl)amino]pyrimidin-4(1H)-one Non sedating antihistamine, once daily Blocks H1 receptor & 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 & throat Used in treating allergic reactions 30

31. H2 Antagonist 31

32. Histamine act on H2 receptor (present on parietal cell of stomach) which in turn activates H+/K+ ATPase system thus more secretion of acid (H 3 O + ) in exchange for the uptake of K + Anti-histamine competitively inhibit action of Histamine on H2 receptors & prevents exchange of acid (H 3 O + ) for K + ,thus preventing activation of H+/K+ ATPase system 32

33. Structural requirements H2 anti-histamines specifically designed to decrease the secretion of gastric acid Cimetidine , in which imidazole ring is maintained (As that of histamine). The imidazole ring is substituted with C-4 methyl group for H2 selectivity, a 4 C side chain includes a S atom (sulfur atom increases potency compared to C & O congeners) & a terminal polar non-basic unit , in this case an N- cyanoguanidine substitution (guanidine substitution with electron withdrawing groups have significantly decreased basicity compared to guanidine and they are neutral at physiological pH) Histamine Cimetidine 33

34. Nitromethylene unit was replacement of N- cyanoimino group in the substituted guanidine analogues affording compounds of increased potency Ranitidine Replacement for the imidazole ring with other hetroaromatic rings resulted in other useful analogue Nizatidine 34

35. 1) Cimetidine N’’- cyano -N-methyl-N’-[2-[[(5-methylimidazol-4-yl)methyl]- thio ]ethyl]guanidine 35

36. Rational designing of Cimetidine 36 Basic electron withdrawing side chain H1 and H2 Agonist Histamine 5-methyl histamine Guanyl histamine H2 Agonist > H1 (5-Me favours H2 receptor selectivity) Basic Weak H2 antagonist (partial agonist)

37. Increase in length of side chain by 2-3 more carbons along with replacement of strongly basic guanidino group by neutral . Methyl thiourea group gives H2 antagonistic activity . 37 Low potency & poor bioavailability becoz of electron releasing –CH3 which favours N ∏ -tautomer ( non pharmacophoric ) (Non basic, electron releasing side chain) Burimamide

38. H2 antagonist of high potency because 5-Me high selectivity S- electronegative grp favours N Ʈ tautomer But thiourea functional group leads to toxicity ,which is eliminated by replacing ‘S’ with cyano-imino function 38 Metiamide Thioether

39. Highly potent Selective H2 antagonist Good oral bioavailability Less toxicity 39 Ci metidine But short acting  need more dosing, also antiandrogenic Hence, need of other backbone is sought

40. Other heterocycles can be tried. If imidazole ring is used then N Ʈ – tautomer is active at H2  Antagonistic effect Seperation of ‘N’ and ring with at least 4 ‘C’ is MUST Thioether link N, bioisosteric N can also be used. Terminal ‘N’ functionality must be  polar, nonbasic Antagonistic effect α 1 Groups which are positively charged at body pH EXCEPTION – 1,1-diamino nitroethene (hydrophilic) in Ranitidine and Azatidine 40

41. Famotidine N-aminosulfonyl-3-(2-diamino methylene)-amino-4-thiazolyl-methyl thio propanimidamide 41

42. 42 Nizatidine Ranitidine

43. Cimetidine reduces hepatic metabolism of drugs biotransformed by CYP450, delaying elimination & increasing serum levels of these drugs Concominant therapy of patients with cimetidine & drugs metabolized by hepatic microsomal enzymes, particularly those of low therapeutic ratio or in patients with renal or hepatic impairment, may require dosage adjustment If concurrent azole therapy is required, it is best to administer it at least 2 hrs before Cimetidine administration. Has weak antiandrogenic effect High oral bioavailability with plasma half life of about 2 hrs which is increased in renal or hepatic impairment & in elderly Cimetidine is metabolized (S-oxidation, 5- CH 3 hydroxylation) & eliminated by renal excretion 43

44. Metabolism of cimetidine Sulfone 5- CH 3 hydroxylation 44

45. 2) Ranitidine N-[2-[[[5-( dimethylamino )methyl]-2-furanyl]methyl] thio ]ethyl]-N’-methyl-2-nitro-1,1-ethenediamine Bioavailability of an oral dose is 50 -60% & is not affected by presence of food Some antacid may reduce it’s absorption & should not be taken within 1hr administration of the H2 blocker Plasma half life is about 2-3hrs & metabolites are excreted in urine 3 metabolites, ranitidine N-oxide, ranitidine S-oxide & desmethyl ranitidine have been identified Weak inhibitor of hepatic CYP450 mixed function oxidase system Ranitidine is used (as bismuth citrate) with macrolide antibiotics ( clarithromycin ) in treating patients with an active duodenal ulcer associated with H.pylori infection 45

46. Metabolism of ranitidine N-oxide desmethyl S-oxide ( sulfoxide ) 46

47. 3) Famotidine N’-( aminosulfonyl )-3-[[[2-( diaminomethylene )-amino]-4-thiazolyl]methyl] thio ] propanimidamide Famotidine is a competitive inhibitor of H2 receptors & inhibits basal & nocturnal gastric secretion as well as secretion stimulated by food & pentagastrin Used for short term treatment of duodenal & benign gastric ulcers, GERD, pathological hypersecretory conditions ( eg . Zollinger -Ellison syndrome) & heartburn Studies with Famotidine in humans, in animals models & in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes ( eg . CYP450 system) 47

48. It is incompletely absorbed and eliminated by renal & metabolic routes Famotidine sulfoxide is only metabolite identified in humans 48 Metabolism of famotidine

49. 4) Nizatidine N-[2-[[[2-( dimethylamino )-methyl]-4-thiazolyl]methyl] thio ] ethyl]-N’-methyl -2-nitro-1,1-ethenediamine Nizatidine has excellent oral bioavailability (>90%) & effects of antacids & food on its bioavailability are not clinically significant Elimination half life is 1-2 hrs Excreted primarily in urine & mostly as unchanged drug Metabolites include nizatidine sulfoxide , N- desmethylnizatidine & nizatidine N-oxide No antiandrogenic action or inhibitory effects on CYP450-linked drug metabolizing enzyme system 49

50. Metabolism of nizatidine desmethyl (less active) N-oxide S-oxide ( sulfoxide ) 50

51. Proton Pump Inhibitor (PPI) The final step in acid secretion in parietal cells of the gastric mucosa is a process mediated by H+/ K+ATPase , the gastric proton pump which catalyzes the exchange of hydrogen ions for potassium ions PPI inhibits gastric acid secretion irrespective of receptor stimulation process These agents have irreversible effects on the secretion of gastric acid, because molecule rearrange in strongly acidic environment of parietal cell Covalent bonding of rearranged inhibitor to H+/ K+ATPase results in inactivation of catalytic function of proton pump One of the site is cystein-813 & these cysteins are in different environment & different PPI’s bind differentially to them & other sulfhydryl groups In covalent binding, disulfide bonds are formed with receptor 51

52. 52

53. 1)Omeprazole 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl) sulfinyl )-1H-benzimidazole 53

54. Omeprazole is an amphoteric compound & is acid labile, hence, it is formulated as delayed release capsule containing enteric coated granule Plasma half life is about 1 hr Most of an oral dose of omeprazole is excreted in the urine as metabolites with insignificant antisecretory activity The primary metabolites of omeprazole are 5-hydroxyomeprazole (by CYP2C19) and omeprazole sulfone (CYP3A4) The antisecretory actions of omeprazole persists 24-72 hrs, long after the drug has disappeared from plasma, which is consistent with its suggested mechanism of action involving irreversible inhibition of proton pump, H+/K+ ATPase. Used in treatment of heartburn, duodenal ulcer, gastric ulcer, etc. 54

55. 2 ) Lansoprazole 2-[[[3-methyl-4-(2,2,2-trifluroethoxy) -2-pyridyl]methyl] sulfinyl ]-1H- benzimidazole Lansoprazole is a weak base (pyridine N, pKa 3.83) and a weak acid ( benzimidazole N-H, pK 0.62) Lansoprazole is essentially a prodrug that, in the acidic biophase of the parietal cell, forms an active metabolite that irreversibly interacts with target ATPase of the pump It is formulated as encapsulated enteric coated granules for oral administration to protect the drug from the acidic environment of the stomach Drug is metabolized in liver ( sulfone and hydroxy metabolites) and excreted in bile and urine with plasma half life of 1.5 hrs 55

56. 3) Rabeprazole 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl] sulfinyl ]-1H-benzimidazole Rabeprazole is a weak base (pyridine N, pKa 4.53) and a weak acid ( benzimidazole N-H, pKa 0.62) It is formulated as enteric coated delayed release tablets to allow the drug to pass through the stomach relatively intact Plasma half life is about 1-2 hrs Metabolized in liver & thioether and sulfone are primary metabolites resulting from CYP3A oxidation, also desmethyl rabeprazole is formed via action of CYP2C19 Eliminated in urine as thioether carboxylic acid and its glucoronide and mercapturic acid metabolites 56

57. 4) Pantoprazole 5-( Difluromethoxy )-2-[[[3,4-dimethoxy-2-pyridinyl]methyl] sulfinyl ]-1H-benzimidazole Pantoprazol is a weak base (pyridine N, pKa 3.96) and a weak acid ( benzimidazole N-H, pKa 0.89) The stability of this compound in Aq. Solution is pH dependent; rate of degradation increases with decreasing pH With food, may delay its absorption but does not alter its bioavailability Metabolized in liver & metabolites are O- demethylation (CYP2C19), sulfur oxidation (CYP3A4) Excreted in urine & feces through biliary excretion 57

58. Metabolism of PPI’s 58

59. 59 SYNTHESIS OF RANITIDINE

60. 60 1,1-bis( methylthionitroethene

61. References: Foye’s Principles of Medicinal Chemistry. Wilson & Grisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry. Textbook of Medicinal Chemistry (vol-1); K.Ilango & P.Valentina ( For synthesis only). 61