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Medicinal chemistry

Medicinal chemistry. Dr. Jehad Harbali IUST College of Pharmacy. Histamine and Antihistaminic Agent. Histamine Histamine life cycle Histamine H 1 Antagonists (antihistaminic agents) Histamine H 2 Antagonists (antihistaminic agents) Histamine H 3 -Receptor Ligands. Histamine.

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Medicinal chemistry

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  1. Medicinal chemistry Dr. Jehad Harbali IUST College of Pharmacy

  2. Histamine and Antihistaminic Agent • Histamine • Histamine life cycle • Histamine H1 Antagonists (antihistaminic agents) • Histamine H2 Antagonists (antihistaminic agents) • Histamine H3-Receptor Ligands

  3. Histamine Introduction: • Histamine is β- imidazolylethylamine derivative that is present in essentially all mammalian tissues. • The major physiological actions of histamine are centered on the cardiovascular system, nonvascular smooth muscle, exocrine glands, and the adrenal medulla.

  4. Histamine • Histamine plays an important role as a “chemical messenger” component of a variety of pathways that have involved in the mediation of allergic and hypersensitivity reactions, and regulation of gastric acid secretion. • This involvement has led to the development of important drug classes useful in the treatment of symptoms associated with allergic and gastric hypersecretory disorders.

  5. Histamine • Nomenclature: Histamine known as 4-(2-aminoethyl) imidazole, structurally is composed of an imidazole heterocycle and ethylamine side chain. Histamine Histamine Rotamers

  6. Histamine • Ionization and Tautomerism:Histamine is a basic organic compound, capable of existing as a mixture of different ionic and uncharged tautomeric species. It exists almost exclusively as the monocationic conjugate species (αNH3+) at physiological PH (7.4). • In aqueous solution, 80% of the histamine monocationic existsas NŢ-H and 20% exists as Nπ-H. • Other studies support the proposal that theNŢ-Htautomer of the histamine monocation is the pharmacophoric species at the H1 receptor, while a 1,3-tautomeric system is important for selective H2-receptor agonism.

  7. Histamine tautomers and cations

  8. Histamine • Histamine Life Cycle: histamine is synthesized in cytoplasmic granules of its principal storage cells, Mast cells and basophiles. Histamine is formed from the naturally occurring amino acid, S- histidine, via the catalysis of either the pyridoxal phosphate-dependent enzymehistidine decarboxylase, or aromatic amino acid decarboxylase. • histamine is found in almost all mammalian tissues in concentrations ranging from 1 to more than 100 µg/g. This substance is in particularly high concentration in skin, bronchial mucosa, and intestinal mucosa. • It is found in higher concentrations in mammalian cerebrospinal fluid than in plasma and other body fluids.

  9. Histamine • Storage and Release:Most histamine is synthesized and stored in mast cells and basophilic granulocytes. Protein- complexed histamine is then stored in secretory granules and released by exocytosis in response to a wide variety of immune (antigen and antibody) and nonimmune (bacterial products, xenobiotics, physical effects, and cholinergic effects) stimuli. • The release of histamine as one of the mediators of hypersensitivity reactions is initiated by the interaction of an antigen- IgE complex with the membrane of histamine storage cell. • This interaction triggers activation of intracellular phosphokinase C (CPK), leading to accumulation of inositol phosphate, diacylglycerols, and Ca2+.

  10. Histamine biosynthesis Histidine Decarboxylase Or Aromatic aminoacid decarboxylase Pyridoxal Phosphate

  11. Storage and Release: • Histamine is released from mast cells in the gastric mucosa by gastrin and acetylcholine. • Neurochemical studies also suggest that histamine is stored in selected neuronal tracts in the central nervous system (CNS). • Receptors: extensive pharmacological analysis suggests the existence of at least three different histamine receptor subtypes, H1, H2 and H3.

  12. Histamine • HistamineH1receptors have been detected in a wide variety of tissues including mammalian brain; smouth muscle from airways, gastrointestinal (GI) tract, genito- urinary system, and the cardiovascular system; adrenal medulla; and endothelial cells and lymphocytes. • HistamineH2receptors have been detected in a wide variety of tissues (including myocardial cells and cell membranes of acid-secreting cells [parietal] of the gastric mucosa) and mediate the gastric acid secretory actions of histamine.

  13. Histamine - Receptors: • The H3 receptor is proposed to function as a neural autoreceptor (presynaptic) serving to modulate histamine synthesis and release in the CNS. • Subsequent studies have also located H3 sites in peripheral tissue, including the gastric mucosa where this receptor may negatively control gastric terminals in the myocardium, acid secretion and on the cardiac sympathetic. • A new histamine receptor, theH4subtype, was first reported in 2000 and characterized as a 390- amino acid.

  14. Histamine • These new receptor exhibits a very restricted localization; expression is primarily found in intestinal tissue, spleen, thymus, immune active cells, neutrophils, and eosinophils, which suggests an important role forH4receptors in the regulation of immune function. • Metabolism: histamine is subject of methylationcatalysed by the enzyme histamine N- methyltransferase (HMT), or the monoamine oxidase (MAO) to give N-methyl histamine, and N-methyl imidazole acetic acid respectively.

  15. Histamine • Histamine is also subject to oxidative deamination by diamine oxidase (DAO),yieldingimidazole acetic acid,a physiologically inactive product excreted in the urine. • Important role: the action ofhistamine that are of interest from both pharmacological and therapeutic point of view include: (a)its important but limited role as a chemical mediator of hypersensitivity reactions. (b)a major role in the regulation of gastric acid secretion.(c)an emerging role as a neurotransmitter in the CNS.

  16. Metabolism of Histamine MAO-B (brain) DAO (periphery) HMT MAO-B (brain) DAO (periphery)

  17. Histamine metabolism MAO-B (brain) DAO (periphery) ALD-DH Histamine HMT N-methylhistamine imidazole acetic acid MAO-B (brain) DAO (periphery) ALD-DH Phosphoribosyltransferase N- methylimidazole acetic acid Imidazole acetic acid Riboside

  18. H1 Anti-Histamine 1 5 • There are five categories of H1 antihistaminic compounds: 2 4 3

  19. H1 Anti-Histamine • Histamine H1 Antagonists (antihistaminic agents):they are drugs that antagonize the actions of histamine at H1 and H2 receptors. They competitively inhibits the action of histamine on tissues containing H1 receptors. • SAR:they are now commonly subdivided into two broad groups, 1st generation, or classical, antihistamines; and 2ed. Generation, or nonsedating antihistamines. Most detailed published SAR focus on the generation structure: Ar R X– (CH2)n– N Ar’ R’

  20. H1 Anti-Histamine • In this structure:Aris aryl (including phenyl, substituted phenyl, and heteroaryl groups such as 2-pyridyl);Ar’is a second aryl or arylmethyl group;Xis a connecting atom ofO, CorN; (CH2)nrepresents a carbon chain, usually ethyl; NRR’represents a basic, terminal amine function. • In many of the first generation, or classical antihistamines, the terminal nitrogen atom is a simple dimethylamino moiety. The amine may also be part of a heterocyclic structure, The carbon chain of typical H1 antagonists consists of two or three atoms. Branching of the carbon chain results in reduction of the antihistaminic activity.

  21. H1 Anti-Histamine • General pharmacological considerations: The classical antihistamines have been used extensively for the symptomatic treatment (sneezing, rhinorrhea, and itching of eyes, nose, and throat) of allergic rhinitis (hay fever, pollinosis), chronic idiopathic urticaria, and a number of other histamine-related diseases. • These uses are clearly attributable to their antagonism of the action of histamine at peripheralH1receptors. The drugs best relieve the symptoms of allergic diseases at the beginning of the season when pollen counts are low. • Although the symptoms of the common cold might be modified by antihistamines. These agents do not prevent or cure colds, nor do they shorten the course of the disease. Pollen: a fine yellow, powder which is formed in flowers itching of eyes:the feeling that makes you want to rub or scratch your eyes. Idiopathic : an unknown the cause.

  22. H1 Anti-Histamine • A number of the antihistamines, particularly the phenothiazines and aminoalkyl ethers, have antiemetic actions and thus may be useful in the treatment of nausea, vomiting, and motion sickness. • Also, those agents that produce pronouncedsedation, (which is attributed to their ability to penetrate the blood-brain barrier), have application as nonprescriptionsleeping aids. • Several of the phenothiazines have limited use in Parkinson-like syndromes as a result of their ability to block central muscarinic receptors. • A number of antihistamines, including promethazine, pyrilamine, tripelennamine and diphenhydramine, display local anesthetic activity that may be therapeutically useful.

  23. H1 Anti-Histamine 1st generation H1-Antagonist Drug Classes: • 1- Aminoalkyl ethers (Ethanolamines): most compounds are simple N,N- dimethylethanolamine derivatives. They have the general structure:R”RAr’—C—O—CH2—CH2—NArR’

  24. 1st generation H1-Antagonist Drug Classes: 1- Aminoalkyl ethers (Ethanolamines):

  25. 1- Ethanolamines - members: ◙Diphenhydramine was the 1st clinically useful member of this series of ethanolamine, and serves as the prototype. Other derivatives have been obtained by para substitution ofmethyl (methyldiphenhydramine), methoxy (medrylamine), chloro (chlorodiphenhydramine), or bromo, (bromodiphenhydramine), on one of the phenyl rings. ◙These derivatives have better therapeutic profiles than diphenhydramine because of reduced adverse effects. Replacement of one of thephenylrings of the diphenhydraminewith a2-pyridylgroup, as inDoxylamineandCarbinoxamine, enhances antihistaminic activity. ◙The most important members are:

  26. 1- Ethanolamines - members: • 1) Diphenhydramine Hydrochloride (BENADRYLR): in addition to antihistaminic action, it exhibits antidyskinetic, antiemetic, antitussive and sedative properties. The usual dose range is from 25 to 400 mg/24h., • It is a highly active H1 antagonist; and it has anticholinergic and sedative properties. It is recommended in various allergic conditions, as anantispasmodic, in the treatment ofurticaria, seasonal rhinitis(hay fever), and somedermatoses. Dyskinetic: difficulty in movement : اختلال الحركة Urticaria:شرى Diphenhydramine HCl

  27. 1- Ethanolamines - members: • 2) Dimenhydrinate :8- Chlorotheophyllinate(THEOCLATER) salt of diphenhydramine, 8- Chlorotheophylline 2-(diphenylmethoxy)-N,N-dimethylethylamine(DRAMAMINER),are recommended for thenauseaofmotion sicknessand fornausea of pregnancy. Usual adult dose : oral, 50-100 mg/4 hours; IM or IV, 50 mg/4 hours; The dose should be taken at least one-half hour before beginning the trip. • Motion of sickness:دوار الحركة، في الطائرة والقطار و .... Dimenhydrinate

  28. 1- Ethanolamines - members: • 3) BromodiphenhydramineHCl (AMBODRYL HClR) : it is twice as effective in protecting guinea pigs against the lethal effects of histamine aerosols. Usual adult dose : oral, 25 mg/4-6 hours. Bromodiphenhydramine HCl

  29. 1- Ethanolamines - members: 4) Doxylamine Succinate (DECAPRYN SuccinateR) :it is comparable in potency to diphenhydramine. It is a good nighttimehypnotic Usual adult dose : oral, 12.5-25 mg/4-6 hours. Doxylamine Succinate

  30. 1- Ethanolamines - members: • 5) Carbinoxamine Maleate (CLISTINR) :it is a potent antihistaminic and is available as the racemic mixture. The more active levo isomer has the (S) absolute configuration. Usual adult dose : oral, 4-8 mg/24 h. • 6) Clemastin Fumarate (TAVISTR) :it is a long acting derivative (5-7 hours, and persists for 10-12 hours). Usual adult dose : oral, 1.34 mg/24 h. or 2.68 mg/24 h. • 7) Diphenylpyraline HCl (HISPRILR, DIAFENR) :it is a potent antihistaminic, and the usual dose is 2 mg/ 3-4 times daily. Usual adult dose : oral, 5 mg/12 h.

  31. 1st generation H1-Antagonist Drug Classes: • 2- Ethylenediamines: they are simple diarylethylenediamines. Phenbenzamine was the 1st clinically useful member of this class and served as the prototype for the development of more effective derivatives. Replacement of thephenylmoiety with a2-pyridylsystem yieldedtripelennamine, asignificantly more effective histamine receptor blocker. • Substitution of a para methoxy (pyrilamine or mepyramine), chloro (chloropyramine), or bromo (bromtripelennamine) further enhances activity. • They are highly effective H1 antagonists, but they also display a relatively high frequency of CNS depressant and GI side effects. ArR N—CH2—CH2—N Ar’R’

  32. 2- Ethylenediamines: Ethylenediamine & Piperazine derives.

  33. 2- Ethylenediamines- members : • 1- Tripelennamine Citrate:these are two salts of this drug, monocitrate and the hydrchloride. Usual adult dose : oral, 25-50 mg/4-6 hours. Tripelennamine Citrate or HCl

  34. 2- Ethylenediamines- members : • 2- Pyrilamine Maleate:clinically, pyrilamine and tripelennamine are considered among the less potent antihistaminics. Because of the pronounced local anesthetic action, the drug should not be chewed, but taken with food. Pyrilamine Maleate

  35. 2- Ethylenediamines- members : • 3- Methapyrilene HCl:the FDA declared this product a potential carcinogen in 1979. Methapyrilene HCl

  36. 2- Ethylenediamines- members : • 4- Antazoline phosphate:It is less active than most of the other antihistaminicdrugs. It can be applied topically to the eye, and it can be used as local anesthetic, and anticholinergic drug. Antazoline phosphate

  37. 2- Ethylenediamines- members : • 5- Thonzylamine HCl:It is similar in activity to tripelennamine but is claimed to be less toxic. The usual dose is 50 mg up to 4 times daily. It is available in certain combination products. Thonzylamine HCl

  38. 1st generation H1-Antagonist Drug Classes: 3- Piperazines (Cyclizines):they are moderately potent antihistaminics with a low incidence of drowsiness. It is claimed for its antiemetic,antinauseants and antivertigo effects. Some members of this series have exhibited a strong teratogenic potential, including a number of malformations in rats. Drowsiness: نعاس General Structure of piperazines

  39. 1st generation H1-Antagonist Drug Classes: 1st generation H1-Antagonist Drug Classes: 3- Piperazines (Cyclizines):

  40. 3- Piperazines (Cyclizines): • 1) Cyclizine HCl (MAREZINER):it is used primarily in the prophylaxis and treatment of motion sickness, by intramuscular injection. Usual adult dose: oral. 50 mg/4-6 hours; IM, 50 mg/4-6 hours. Cyclizine HCl or Lactate

  41. 3- Piperazines (Cyclizines): • 2) Chlorcyclizine HCl:it is indicated in the symptomatic relief of urticaria, hay fever, and certain other allergic conditions. Chlorcyclizine HCl

  42. 3- Piperazines (Cyclizines): • 3) Meclizine HCl: it is a moderately potent antihistaminic, and it is used as an antinauseant in the prevention and treatment of motion sickness, nausea and vomiting associated with vertigo and radiation sickness.Usual adult dose: oral. 25-50 mg/24 h. • 4) Buclizine HCl (BUCLADIN-SR): Usual adult dose 50 mg 30 minutes before travel and is repeated in 4 to 6 hours as needed. Meclizine HCl

  43. 1st generation H1-Antagonist Drug Classes: • 4- Propylamines (Monoaminopropyl derivatives):those compounds are commonly referred to as the pheniramines. All of the pheniramines consist of a phenyl and a 2-pyridyl aryl group and a terminal dimethylamino moiety. This compounds differ only in the phenyl substituent at the para position —H (Pheniramine), Cl (Chlorpheniramine), and Br (Brompheniramine). • The halogenated pheniramines are significantly more potent (20 to 50 times) and have a longer duration of action. They produce less sedation than the other classical antihistamines, and have significant anticholinergic and little antiemetic actions.

  44. 1st generation H1-Antagonist Drug Classes: 4- Propylamines derivatives:

  45. 4- Propylamines - members: • 1. Pheniramine Maleate (TRIMETONR, INHISTONR):it isthe least potent member of the series and is marketed as the racemate; the usual adult dose is 20 to 40 mg 3 times daily, it is available in certain combination products.

  46. 4- Propylamines - members: • 2. Chorpheniramine Maleate (CHLOR-TRIMETONR):it has a half-life of 12 to 15 hours, andthe usual dose is 2 to 4 mg 3 times a day. Dosage forms: e-r. capsules, syrup, tablets, chewable tablets, e-r. tablets, injection. • 3. Dexchorpheniramine Maleate (POLARAMINER):it is the dextrorotatory enantiomer of Chorpheniramine.the usual adult dose: oral, 2 mg /daily. Dosage forms: Syrup, tablets, e-r. tablets.

  47. 4- Propylamines - members: • 4. Brompheniramine Maleate (DIMETANER): it has a half-life of 25 hours.The usual adult dose: oral, 4 mg /daily; extended-release, 8-12 mg/8-12 hours; IM,IV, or SC, 10 mg/ 8-12 hours. Dosage forms: Elixir, tablets, e-r. tablets, injection.

  48. 4- Propylamines - members: • 5. Dexbrompheniramine Maleate (DISOMERR): • 6. Pyrrobutamine Phosphate (PYRONILR): • 7. Triprolidine HCl (ACTIDILR): similar to dexchlorpheniramine. The peak effect occurs about 3.5 hours after oral administration, and the duration of effect is about12 hours. • 8. Phenindamine Tartrate : it may produce drowsiness and sleepiness; it may also cause a mildly stimulating action in some patients and insomnia when taken just before bedtime.The usual adult dose: oral, 25 mg /4-6 hours. Dosage forms: tablets.

  49. 1st generation H1-Antagonist Drug Classes: • 5- Phenothiazines :they are useful antihistaminic, that display an antipsychotic activity. promethazine, the parent member of this series, is moderately potent, with prolonged action and pronounced sedative side effects. In addition to its antihistaminic action, it is a potent antiemetic, anticholinergic, and sedating agent and significantly potentiates the action of analgesic and sedative drugs. The other members of this series are:

  50. 1st generation H1-Antagonist Drug Classes: • 5- Phenothiazines :

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