Pharmaceutical Chemistry Lecture 2 PDF

PHARMACEUTICAL CHEMISTRY III LECTURE 2 PROF. DR. ASHRAF ABADI PHCMt774 Prof. Ashraf Abadi 1  BY THE END OF LECTURE 2, THE STUDENT WILL BE ABLE TO: Domain 1: Fundamental Knowle...

PHARMACEUTICAL CHEMISTRY III LECTURE 2 PROF. DR. ASHRAF ABADI PHCMt774 Prof. Ashraf Abadi 1  BY THE END OF LECTURE 2, THE STUDENT WILL BE ABLE TO: Domain 1: Fundamental Knowledge 1-1- Competency Key Elements 1-1-1 Demonstrate knowledge of the metabolic pathways of Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators. 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 the Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators, including mechanisms of actions, therapeutic uses, dosage, contra-indications and drug interactions. 1-1-5 Show the relationship between the properties of Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators 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 Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators and their activity (Structure-Activity Relationship), safety/toxicity profile. 2-2-2 Select the appropriate methods of synthesis, purification, and identification of Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators. 2-2-3 Apply the pharmacological basics of therapeutics in the proper selection and use of drugs in various disease conditions. 2-2-4 Weigh activity versus side effects of Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators, 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 Beta-Blockers, Amine Depletors, Ganglionic blockers and Direct Vasodilators, deduced from their structure & metabolism. Domain 4: Personal Practice 4-1- Competency Key Elements 4-1-3 Demonstrate critical thinking, and problem solving regarding solving extra exercises in tutorials, assignments, and 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 each drug. 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 2  BETA- BLOCKERS: RECEPTORS & USES  There are three types of β-receptors:  β1: located mainly in the heart, activation  Increase in cardiac output.  β2: Mainly lungs and smooth muscle, activation  associated with side effects of antihypertensive beta blockers, mainly bronchospasm (beta blockers are contraindicated in asthmatic patients).  β3: mainly in adipose tissue  we don’t have drugs working on this receptor subtype.  Blocking the action of endogenous norepinephrine and epinephrine on β1- adrenoreceptors in the heart, resulting in negative inotropic, negative chronotropic effects, leading to a decrease in cardiac output and oxygen demand. They also inhibit renin release, angiotensin II and aldosterone production, and lower peripheral resistance. They also inhibit peripheral conversion of T4 to the more active T3.  Beta blockers are mainly used as antihypertensive, antianginal and antiarrhythmic agents. PHCMt774 Prof. Ashraf Abadi 3  BETA- BLOCKERS: RECEPTORS & USES  Treating hypertension with preexisting conditions such as previous myocardial infarction, angina pectoris.  Individual beta blockers produce varying degrees of bradycardia, e.g. acebutolol and pindolol are of ISA (partial agonist) properties. Used when severe bradycardia is to be avoided.  Supportive in the treatment of arrhythmia associated with hyperthyrodism and phaeochromocytoma.  Prophylactic in migraine and aggressive behavior (lipophilic members, log P> 2)  Applied to the eye to treat glaucoma (β-receptors are involved in the formation of aqueous humor). They do not affect the pupil size. Timolol and levobunolol are of particular value.  Off-label usage includes management of post-traumatic stress disorder (wars, rape,…etc); counteracting stage fright, minimizing hand tremors and doping agent in sport. PHCMt774 Prof. Ashraf Abadi 4  DISCOVERY OF ΒETA-BLOCKERS HO NH Cl HO HO NH NH OH Cl HO OH OH Dichloroisoprotrenol Isoprotrenol-Isoprenalien Adrenaline Non-selective beta- agonist beta-partial anatgonist alpha beta agonist HO NH2 HO OH O NH NH Noradrenaline OH OH mainly alpha agonist Propranolol Pronethalol Full beta antagonist and devoid of beta-partial antagonist carcinogenic effect but carcinogenic  Sir James W. Black, Scottish pharmacologist, The Nobel Prize in Physiology or Medicine 1988. He discovered propranolol 1964, discovered cimetidine 1975, and set the principle of “Endogenous Chemical Mediators as a tool in Drug Discovery”.  Black was appointed professor, and head of department, of pharmacology at University College London in 1973 where he established a new undergraduate course in medicinal chemistry. PHCMt774 Prof. Ashraf Abadi 5  CLASSES OF ΒETA-BLOCKERS NON-SELECTIVE BETA-BLOCKERS O O O S OH O N H HN N * NH O NH O NH N O * OH OH S N OH Propranolol Sotalol Levobunolol Timolol (Inderal) (Betacor) (Betagen) (Timoptic) (RS)1-Isopropylamino-3-(1- naphthyloxy)-2-propanol PHCMt774 Prof. Ashraf Abadi 6  SELECTIVE BETA1-BLOCKERS O O H2N O O NH HN O NH * O O NH O * * OH OH OH Atenolol Esmolol Acebutolol (Tenormin) (Brevibloc) (Sectral) F NH F O O O * O * * N * * OH H O OH OH Bisoprolol Nebivolol (Concor) (Nebilet) PHCMt774 Prof. Ashraf Abadi 7 MIXED ALPHA1 BETA-BLOCKERS Labetalol Carvedilol (Trandate) (Carvid) PHCMt774 Prof. Ashraf Abadi 8  SAR OF ΒETA-BLOCKERS  The aromatic moiety  All beta blockers are Arylethanolamine (sotalol, labetalol) or aryloxypropanolamine derivativaes e.g. propranolol i.e. Y is absent or = OCH2, respectively.  The nature of the aromatic ring (aryl, heteroaryl) and its substituents are the main determinants of β-receptors blocking activity, β1-selectivity, absorption, excretion, metabolism, and CNS side effects. Selective β1-antagonists possess a para substitued aryl and an unsubstituted meta position, However, in clinical settings, selectivity may be lost and all beta blockers are contraindicated in asthmatic patients. β-Blockers with hydrophilic substituents are of lower penetrability to the CNS and lower CNS side effects or usage for prophylaxis from migraine. Log P values: Propranolol (log p = 3.65; atenolol log p = 0.23). PHCMt774 Prof. Ashraf Abadi 9  SAR OF ΒETA-BLOCKERS Esmolol is of very short t1/2 only 9 minutes, due to its rapid hydrolysis by esterase enzyme to the inactive carboxylic acid derivative. It is given as IV infusion to control ventricular and atrial fibrillation (not hypertension). Acebutolol is metabolized by hydrolysis of the amide followed by acetylation to give diacetolol which is as active as the parent drug (long acting). Acebutolol is of ISA (partial antagonist) and used whenever bradycardia is to be avoided.  The amino function is  Substituted by bulky aliphatic group e.g. tert-butyl or isopropyl groups (Z = H or CH3) as in sympathomimetics.  A secondary amine for optimal activity.  β-Blockers are mostly used as salts. Their free bases are mostly of low melting (m. p of metoprolol = 45 oC), thus difficult to work with in a manufacturing Environment. The salts are usually of m. p. > 100 oC. 10 PHCMt774 Prof. Ashraf Abadi  SAR OF ΒETA-BLOCKERS  Chirality  The asymmetric carbon is mostly of the S configuration for optimal β- antagonistic activity. However, most of the beta blockers are marketed as racemates. The only exception are levobunolol and timolol whereby only the S enantiomer is marketed.  Labetalol (4 isomers), the RR isomer is responsible for beta blocking, meanwhile the SR (benzylic, aliphatic, respectively) isomer is responsible for alpha blocking; the SS and RS isomers are inactive. Some patients with CHF may benefit from the combined α, β blocking, vasodilatation, antihypertensive effect without tachycardia.  Carvedilol: S isomer blocks beta, whereas R isomer blocks both α1and β.  Nebivolol molecule contains four chiral centers and is marketed as a racemate of (-) Nebivolol (RSSS) and (+) Nebivolol (SRRR). Nebivolol antihypertensive activity resides in the R-enantiomer. Two of the four chiral centers in nebivolol are part of a ring structure and the increased rigidity of this structure may be related to its divergence from the standard pharmacophore model of β–blockers. PHCMt774 Prof. Ashraf Abadi 11  SAR OF ΒETA-BLOCKERS  Chirality e.g. S (-) propranolol Versus R (+) enantiomers Antiarrhythmic activity S (-) > R (+) eudismic ratio >100 Protein binding R (+) > S (-) Clearence S (-) > R (+) Metabolism S (-) by glucuronidation; R (+) by para hydroxylation Sperm motility Depressed mainly by the R (+) male contraceptive!!! Hyperglycemia R (+) > S (-) PHCMt774 Prof. Ashraf Abadi 12 SYNTHESIS OF PROPRANOLOL PHCMt774 Prof. Ashraf Abadi 13  AMINE DEPLETORS GUANATHIDINE (ISMELIN) 1-(2-(azocan-1-yl)ethyl)guanidine  Guanethidine inhibits NE reuptake, thus depleting it from nerve terminals or inhibit its release on stimulation. It only act peripherally due to its guanidine moiety. PHCMt774 Prof. Ashraf Abadi 14  GANGLIONIC BLOCKERS TRIMETAPHAN CAMSYLATE (ARFONAD)  Blocks postsynaptic nicotinic receptor at the sympathetic and parasympathetic ganglia, thus preventing acetylcholine depolarization.  Structurally similar to the neurotransmitter (acetylcholine). Positively charged atom and a carbonyl that are 3 atoms apart from each other.  Sulfonium compound, cannot cross the BBB.  It is used IV to induce controlled hypotension in particular neurosurgery operations. It is of short duration of action. It is of severe side effects e.g. excessive orthostatic hypotension, sexual dysfunction, constipation, urinary retention, dry mouth, precipitation of glaucoma. PHCMt774 Prof. Ashraf Abadi 15  DIRECT VASODILATORS (K+ CHANNEL ACTIVATORS)  They relax smooth muscle of arterioles and sometimes veins, thereby reduce systemic vascular resistance. K+ channel agonists.  Hydralazine SAR: hydrazino should be at position 1. used as its monohydrochloride salt. its effect is most pronounced on diastolic blood pressure.  Diazoxide: replacing the hydrogen at position 6 with free sulfonamide leads to strong diuresis and decrease in BP. Hyperglyceimia is a potential side effect of diazoxide. PHCMt774 Prof. Ashraf Abadi 16  DIRECT VASODILATORS (K+ CHANNEL ACTIVATORS)  Sodium nitroprusside: is given only parenterally, in hypertension emergencies.  Onset 2 min, effect last for 10 min after discontinuation.  It is metabolized to the active species nitric oxide (NO) and the toxic species cyanide (CN) and thiocyanate (SCN). Thus should be used with care in patients with renal failure (cumulative effect).  Solutions of sodium nitroprusside decompose when exposed to light and must be protected during infusion by wrapping the container with aluminium foil or some other light-proof material. (blue color solution indicates decomposition).  Minoxidil: its active form is minoxidil sulfate (N-OSO3-). It is also applied topically as 5% lotion to promote hair growth (hypertrichosis) and correction of baldness. PHCMt774 Prof. Ashraf Abadi 17  TREATMENT OF CYANIDE TOXICITY Cyanide displaces the hydroxo ligand of hydroxocobalamin, converting the cyanide to the much less toxic cyanocobalamin. PHCMt774 Prof. Ashraf Abadi 18  SYNTHESIS OF MINOXIDIL Cl Cl N m-chloroperbenzoic acid N N N H N H2N N NH2 + H2N N NH2 H2N N NH2 - O O SYNTHESIS OF SODIUM NITROPRUSSIDE www.slido.com with #136519 PHCMt774 Prof. Ashraf Abadi 19