Chapter 3.4 Antihistamines

Histamine H 1 Antagonists The term antihistamine historically refers to drugs that antagonize the actions of histamine at H 1 receptors. Histamine is an important chemical mediator of hypersensitivity

4 (5-)-(2-aminoethyl)imidazole

4(5)-(2-aminoethyl) imidazole (a) N  -tautomer (a) N  -tautomer Side chain N = N 

At pH 7.4, histamine exists almost exclusively (96.6%) in a monocationic form Most histamine is synthesized and stored in mast cells and basophilic granulocytes Histamine is mediated by specific cell surface receptors (H 1, H 2, and H 3 ) Properties and Action of Histamine

Biosynthesis and metabolism of histamine histidine decarboxylase histamine N-methyl transferase MAO (brain) DAO (peripheral) Aldehyde dehydorgenase N-methyl histamine imidazolyl acetic acid MAO (brain) DAO (peripheral) Aldehyde dehydorgenase ribose phosphate transferase N-methylimidazolyl acetic acid Imidazolyl acetic acid necleoside

Classification of H1 receptor antagonists lipophilic aromatic moiety diamines piperazines aminoethers Propylamine Piperdines tricyclics

Histamine H1 Receptor Antagonists –ethyl diamines –aminoethers –propylamines ： chlorphenamine maleate –tricyclics ： loratadine –piperazines ： cetirizine hydrochloride –piperidines ： mizolastine –others

Ethyl diamines H1 receptor antagonists Ar = Ph 、 p-subPh or thtiophenyl ； Ar’= Ph or 2- pyridinyl ， R and R’ = Me or heterocyclyl 。 Weaker action to H1 receptor ， moderate central analgesic effect ， causing disorder of gastrointestine ， local external use may cause skin hypersensity.

Aminoethers H1 receptor antagonists If Ar （ Ar ） CHO- replace ArCH2 （ Ar’ ） N- moiety in ethyl diamines, then you get aminoethers. The first generation of H1 receptor antagonist display apparent analgesic and anticholinergic effects ， usually with side reaction like somnolence, dizzy, oral dryness. But incidence rate of gastrointestine reaction is low. Some of drugs could be applied in the treatment of insomnia. For those aminoether with two aromatic group ， the activity of S- isomer is usually higher than that of R-isomer.

Antihistamine drugs without analgesic effect belonged to aminoether type ， they have higher selectivity to peripheral H1 receptor, belong to second generation antihistamine drug. Clemastine Setastine Aminoethers H1 receptor antagonists

Propylamines H1 receptor antagonists When ArCH 2 (Ar)N- in ethyldiamines is replaced by Ar(Ar)CH- moiety ， or omitted -O- in aminoether, then propylamine is there. Compared to traditional antihistamines like ethyldiamines, aminoethers, tricyclics ， propylamines have stronger antihistamine action but weaker central analgesic, and less tendency of inducing somnolence.

Chlorphenamine is an first-generation antihistamines Chlorphenamine Maleate

Action of Chlorphenamine Maleate Stronger antihistamine action ， less dosage ， less side effect ， suitable for children. Mainly use for hypersensitive nasitis, skin mucosa hypersensitivity, urticaria, angiectatic nasitis, hay fever ， contact dermatitis and hypersensitivity caused by food and drugs. Side effect: somnolence, thirsty, diuresis.

Points Need Your Concerns One chiral center in Chlorphenamine ， there is a pair of optical isomer. The activity of S-isomer is twice stronger than that of racemate ， acute toxicity is also less. The activity of R-isomer is only 1/90 than that of racemate 。 In clinic, racemate chlorphenamine maleate is used 。

Chemical Synthesis

Propylamines H1 receptor antagonists Allyl acid make the compound more hydrophilic and it is more difficult for it to enter into central nerve system.Therefore, acrivastine displays no analgesic effect. The activity of E-isomer is great higher than that of Z-isomer. Acrivastine

Tricyclics H1 receptor antagonists If fused together the adjacent position of two aromatic ring, tricyclics H1 receptor antagonist is there. If X = N ， Y = S ， then phenothiazine If X= C (sp2) ， Y is replaced with bioisostere, -CH=CH- ， then cyproheptadine Further modification of cyproheptadine produce loratadine

Loratadine Strong selective H1 receptor antagonist, but no anticholinergic activity and central nerve system inhibition, belong to second generation non-sedative antihistamines. The main difference compared to other tricyclics antihistamines, is the replacement of neutral aminoformate for basic tertiary amine. It is believed this is the reason of its decrease of central analgesic.

Chemical Synthesis of Loratadine

Piperazines H1 Receptor Antagonists When Ar （ Ar ） CHN- replaces ArCH 2 （ Ar ） N- moiety in ethyldiamine, and make two nitrogen atom in piperazine ring, then the piperazines antihistamines are constructed Other than stronger H1 receptor antagonism effect ， they display other characteristic ， like relieving asthma effect, anti- kinetia action, and blocking action of Ca 2+ ion channel.

Cetirizine Hydrochloride Because of the easy ionization of Cetirizine, the drug is not easy to permeate blood brain barrier (BBB), little amount of the drug is able to arrive central nerve system, it belongs to non-sedative antihistamine, it is one of the representative drug of second generation antihistamines.

The advantages of Zyrtec is that 1.Once-daily dosing 2.Rapid onset of activity (20-60 min) 3.Minimal CNS effects

Process for Synthesizing Cetirizine Hydrochloride

Piperidines H1 Receptor Antagonists Limitation of the entrance to central and increase the selectivity to H1 receptor, is the guiding ideology for design and searchin new antihistamine drugs. This resulted in the development of non-sedative H1 receptor antagonists. Clemastine （ aminoethers ）、 Acrivastine （ propylamines ）、 Loratadine （ tricyclics ）, and Cetirizine （ piperazines ） all belong to non-sedative H1-receptor antihistamines. Via the introduction of hydrophilic group, the drug is difficult to enter central nerve system because of BBB, therefore the sedative effect is overcome (weakened). Whilst Clemastine and Loratadine have higher selectivity to peripheral H1 receptor, therefore avoid side effect to Centrum. Other non-sedative antihistamine drugs belong to piperidines selective peripheral H1-receptor antagonists.

Mizolastine 2-[[1-[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2- yl]-4-piperidinyl]methylamino]-4(1H)-pyrimidinone 2- 〔〔 1- 〔 1- 〔（ 4- 氟苯基）甲基〕 -1H- 苯并咪唑 -2- 基〕哌啶基 -4- 基〕甲基氨基〕嘧啶 -4 （ 3H ） - 酮

Process for Synthesizing Mizolastine

SAR of Antihistamines X = O, C, or N N = 2 or 3 lipophilic aromatic moiety diamines piperazines aminoethers Propylamine Piperdines tricyclics