Pharmaceutical Chemistry III Lecture 10 PDF

PHARMACEUTICAL CHEMISTRY III LECTURE 10 PROF. DR. ASHRAF ABADI/DR. MIRNA VICTOR PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 1  BY THE END OF LECTURE 10, THE STUDENT WILL BE ABLE TO: Domain 1: Fundamental Knowledge 1-1- Competenc...

PHARMACEUTICAL CHEMISTRY III LECTURE 10 PROF. DR. ASHRAF ABADI/DR. MIRNA VICTOR PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 1  BY THE END OF LECTURE 10, THE STUDENT WILL BE ABLE TO: Domain 1: Fundamental Knowledge 1-1- Competency Key Elements 1-1-1 Demonstrate knowledge of the specific pathways of H1 antagonists metabolism. 1-1-2 Integrate the theoretical concepts and methodology of different principles of drug design (Structure-based/ Ligand-based). 1-1-3 Use the proper pharmaceutical & medical terms, abbreviations & symbols in pharmaceutical chemistry practice. 1-1-4 Articulate knowledge about various properties of H1 antagonists, including mechanisms of actions, therapeutic uses, dosage, contra-indications and drug interactions. 1-1-5 Show the relationship between the properties of H1 antagonists and their chemical structure including the relationship between physicochemical properties and activity of various drugs. 1-1-6 Utilize scientific literature, and collect and interpret information to enhance professional decision. Domain 2: Professional & Ethical Practice 2-2- Competency Key Elements 2-2-1 Correlate between essential pharmacophoric features of H1 antagonists and their activity (Structure-Activity Relationship), safety/toxicity profile. 2-2-2 Select the appropriate methods of synthesis, purification, and identification of H 1 antagonists. 2-2-3 Apply the pharmacological basics of therapeutics in the proper selection and use of H 1 antagonists in various disease conditions. 2-2-4 Weigh activity versus side effects of H1 antagonists, design of novel medicinal agents, and suggest suitable dosage forms based on the chemical features of drugs. 2-4- Competency Key Elements 2-4-4 Recognize the activity & toxicity profile of H1 antagonists, deduced from their structure & metabolism. Domain 3: Pharmaceutical Care 3-2- Competency Key Elements 3-2-1 Integrate the different synthetic and analytical techniques for synthesis and analysis of H 1 antagonists. Domain 4: Personal Practice 4-1- Competency Key Elements 4-1-3 Demonstrate critical thinking, and problem solving regarding solving extra exercises in lecture slides. 4-2- Competency Key Elements 4-2-1 Demonstrate critical thinking, problem solving and decision making regarding the activity, suitable use and delivery route of H1 antagonists. 4-2-2 Communicate clearly by verbal means through tutorial discussions and implement writing skills through taking notes in lectures. 4-3- Competency Key Elements 4-3-1 Practice independent learning needed for continuous professional development via exploring the references indicated in the lecture slides. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 2  H1 Antagonists (Antihistaminic Agents) Reversible blockers of histamine H1 receptors, mostly in skin, bronchi, intestine,…etc. Uses ✓ Symptomatic relief of hypersensitivity reactions, including urticaria, angioedema rhinitis, conjunctivitis, hay fever, drug allergy, pruritus and eczema. ✓ Pre-anesthestic medication and short management of insomnia e.g. Diphenhydramine and Promethazine. ✓ Parkinson’s disease e.g. Diphenhydramine (anticholinergic). ✓ Control nausea and vomiting associated with vertigo, vomiting of Meniere’s disease, migraine and other vestibular disorders e.g. Dimenhydrinate, Cyclizine and Promethazine. ✓ Migraine prophylaxis and appetizers e.g. Cyproheptadine, Pizotifen (mixed antihistamine, anti 5-HT). ✓ Local anesthetics e.g. Antazoline. ✓ Ineffective in asthma, acute anaphylaxis, and blood transfusion reactions. ✓ Topical antihistamines possess the risk of skin sensitization. ✓ Cause CNS depression (first generation, classic, sedating antihistamines), newly developed antihistamines (second generation, non-classic, non-sedating). PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 3  Classification of H1-Antihistamines First Generation Antihistamines 1. Propylamine or Alkylamine Derivatives 2. Aminoalkyl Ethers (Ethanolamine Derivatives) 3. Ethylenediamine Derivatives 4. Piperazines, Cyclizines 5. Tricyclic Ring System Derivatives Second Generation Antihistamines PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 4 SAR of first generation (classic) Antihistamines Ar' R X (CH2)n N Ar R' PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 5  SAR of first generation (classic) Antihistamines 5-6 Ao 2 Aryl Functions ✓ 2 Aryl functions, connected to a central C, N or C-O or C-N or by a central 7 membered ring (alkylamine, ethanolamine, ethylenediamine (piperazine), tricyclic antihistamines. Ar = phenyl, substituted phenyl, heteroaryl; Ar` = second aryl, or arylmethyl group. ✓ The 2 aryls must adopt a non coplanar conformation relative to each other for optimal interaction with the H1 receptors. Tricyclic ring system is slightly puckered and the two aromatic rings lie in different geometrical planes. ✓ Substituents on one of the aryls influence the antihistaminic potency/ biodisposition. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 6  SAR of first generation (classic) Antihistamines Spacer ✓ Antihistamines with chiral carbon in the connecting moiety exhibit stereoselective receptor binding. Usually (not always) activity is associated with the S-enantiomer (stereoselective interaction). ✓ Spacer between the diaryl and the amine is 2-3 carbons = 5-6 A0. ✓ The spacer may be linear, branched, cyclic, unsaturated. ✓ Branching of the carbon chain is associated with decrease in activity (promethazine is an exception). ✓ Branching may lead to asymmetry near the terminal N, of little effect upon activity (non- steroselective interaction). ✓ Derivatives of unsaturated carbon chain lead to Z and E activity is associated with one of the geometric isomers. Ar' R X (CH2)n N Ar R' PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 7  SAR of first generation (classic) Antihistamines Basic N ✓ NRR’ = basic, terminal amine function e.g dimethylamino moiety or a part of a heterocyclic structure e.g. piperazine, pyrrolidine, imidazoline or piperidine. ✓ Basic nitrogen with pKa value ranging form 8.5-10, protonated at pH 7.4. Important in the development of stable, solid dosage forms (HCl or maleate salt). ✓ Required for binding to muscarinic, adrenergic and serotonergic receptors (side effects). ✓ N-dealkylation is a major metabolic pathway. ✓ Bulkiness of N substituent on the tertiary nitrogen, reflects the structural differences between antagonistic versus agonistic actions at H1 receptors; and second generation versus first generation. Ar' R X (CH2)n N Ar R' PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 8 Alkylamine, Propylamine, Pheniramine Antihistamines PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 9  Aminoalkyl Ethers (Ethanolamines) ✓ Considerable sedative (sleeping-aid) and anticholinergic actions (treatment of Parkinson’s disease). ✓ Replacement of one of the phenyls of Diphenydamine with 2-pyridyl results in Doxylamine and Carbinoxamine that are 40 and 2 times as active as Diphenhydramine. (WHY?) PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 10  Aminoalkyl Ethers (Ethanolamines) Synthesis of Diphenhydramine and Dimenhydrinate Dimenhydrinate? Diphendydramine Derivatives 11 PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor  Ethylenediamine Derivatives Monoacidic salts! ✓ Simple Diarylethylenediamines with nitrogen atom and a 2 carbon chain as the spacer. The aliphatic amino group is more basic than the nitrogen bonded to the diaryl moiety. ✓ For Antazoline, the terminal amine and a portion of the carbon chain are included as part of the imidazoline ring. ✓ Antazoline is of potent CNS depressant, local anaesthetic and anticholinergic properties as well. o The more soluble Antazoline phosphate is used in the eye allergic conditions. o Antazoline hydrochloride is used as oral antihistamine. PHCMt774 Prof. Ashraf Abadi /Dr. Mirna Victor 12  Ethylenediamine Derivatives Synthesis of Mepyramine PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 13  Piperazines, Cyclizines Dihydrochloride salts! ✓ Cyclic ethylenediamine derivatives. The connecting moiety is CH-N. The nitrogen of the connecting moiety, the carbon chain and the terminal amine function are all part of a piperazine moiety. ✓ The main structural differences within the series involve the nature of the para aromatic substituent and the terminal piperazine nitrogen substituent. ✓ Both nitrogens are aliphatics and of comparable basicity. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 14  Piperazines, Cyclizines ✓ They are of peripheral and central antimuscarinic (anticholinergic) actions. They diminish vestibular stimulation and act on the CTZ. Used as moderate antihistamines, indicated for nausea, vomiting and dizziness associated with motion, radiation sickness, vertigo but not pregnancy emesis. ✓ Hydroxyzine is metabolized to Cetrizine (second generation). ✓ Metabolized by N-dealkylation. The metabolite Norchlorcyclizine is teratogenic thus the whole class is contraindicated in pregnancy vomiting. ✓ Chlorcyclizine is repurposed for the treatment of HCV. Hydroxyzine is of sedating and anticholinergic side effects, useful in psychoactive eczema and hallucinogenic if overdosed. Also used as opioid potentiator. ✓ Cyclizine was a space antiemetic for the first occupied moon flight. ✓ Cyclizine dihydrochloride…….Tablet; Cyclizine lactate, more soluble…….injections. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 15  Piperazines, Cyclizines Synthesis of Cyclizines X = H Cyclizine X = Cl Chlorcyclizine PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 16 Tricyclic Ring System Derivatives ✓ Anti-serotonergic ✓ It prevents ✓ Anti-serotonergic effects: bursting of mast effects: 1. Used as an cells, used 1. Used as an appetizer between appetizer 2. Prevention of asthmatic 2. Prevention of Migraine attacks. Migraine PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 17  Tricyclic Ring System Derivatives ✓ Promethazine: Phenothiazine derivative of antihistaminic, antiemetic and CNS sedating actions. The tranquilizing action can be enhanced at the expense of the antihistaminic action through the insertion of a halogen at position 2 or the use of a dimethylaminopropyl rather than an ethyl side chain. ✓ Dibenzocycloheptenes and Dibenzocycloheptanes may be regarded as phenothiazine isosteres in which the S atom is replaced by an isosteric vinyl or a saturated bridge. The nitrogen atom may be replaced by an SP2 carbon atom e.g. Azatadine, Cyproheptadine, Ketotifen and Pizotifen. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 18  Synthesis of Cyproheptadine 5H-dibenzo[a,d]- cyclohepten-5-one PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 19  Second generation, Non-Sedating Antihistamines CNS permeability is mainly a function of: Degree of ionization; Protein binding; Degree of Lipophilicity and Molecular volume. Second generation antihistamines are characterized by: 1. Basic structural features of H1 antagonists are present but with bulky nitrogen substituent of ionizable side substituent. 2. Long acting due to the formation of active metabolite, high PPB, bulky in size and ionizable. 3.Improved peripheral H1 selectivity and little affinity to the central muscarinic, adrenergic and serotonergic receptors and therefore display lower degree of side effects. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 20 Second generation, Non-Sedating Antihistamines PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 21 Second generation, Non-Sedating Antihistamines Metabolism by CYP3A4 & CYP2D6 ✓ Descarboethoxyloratadine. ✓ Desloratadine is a more potent H1 antagonist. ✓ Considered a more potent inhibitor of histamine release. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 22 Second generation, Non-Sedating Antihistamines PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 23  Second generation, Non-Sedating Antihistamines Synthesis of Terfenadine PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 24 Molecular Volume, Functional activity and Crossing the BBB PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 25  Inhibitors of Histamine Release ✓ Cromolyn is a bischromones derivatives. ✓ It prevents the release of histamine , leukotrienes, prostaglandins and other inflammation mediators following immunoglobin binding on mast cells (prevents mast degranulation). ✓ Used in prevention of seasonal asthma attacks and allergic rhinitis available as inhaler and eye drops. ✓ Used as disodium salts in eye drops for treatment of allergic conjunctivitis and as nebulized and aerosol Cromolyn for prophylactic management of bronchial asthma. PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 26  Inhibitors of Histamine Release Synthesis of Cromolyn PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor 27  28 PHCMt774 Prof. Ashraf Abadi/ Dr. Mirna Victor