Medicinal Chemistry Resources (PDF)

Resources For Medicinal Chemistry 1. Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry. Wilson, Charles Owens 1911-; Beale, John Marlowe; Block, John H. c2011 2. Foye's principles of medicinal chemistry Foye, William O.; Lemke, Thomas L. c2008 3. An introduc...

Resources For Medicinal Chemistry 1. Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry. Wilson, Charles Owens 1911-; Beale, John Marlowe; Block, John H. c2011 2. Foye's principles of medicinal chemistry Foye, William O.; Lemke, Thomas L. c2008 3. An introduction to medicinal chemistry Patrick, Graham L. author. 2013 4. Medicinal Chemistry, Norma Dunlap, Donna Huryn, 2018 by Garland Science, Taylor & Francis Group, LLC (some figures) 1  Medicinal Chemistry For Pharmacy Describe mechanism of action of drug: – pharmacological and chemical – molecular interactions between drug and target Understand how the drug was discovered / designed Explore structure-activity relationships for the drug class, – What properties were enhanced? – What properties were lost? Probe Adsorption, Distribution, Metabolism, Excretion (ADME) from a chemical perspective – Structurally where does metabolism occur, how, and what are the consequences. Is the drug a pro-drug? – If so, why? how is it activated chemically Explain to non-science expert how and why the drug functions 2  Case 5 Glaucoma Timolol – beta-adrenergic antagonists Latanoprost – PGF2a analogues Brimonidine – alpha adrenergic agonists Pilocarpine, Carbachol – cholinergic agonists Dorzolomide – carbonic anhydrase inhibitors PHAR1051Module9 (Timolol, 3d4s, Dorzolamide, 4m2u) https://youtu.be/gG1-yfq5cx0 3  Adrenergic Receptors Type A GPCRs Two types of adrenoceptor (α and β) Subtypes (α1 and α2; β1, β2 and β3) Subtypes of subtypes (α1A α1B α1D α2A α2B α2C) G-protein coupled receptors Tissue specific receptors 4  Drug Discovery of Timolol Selectivity for beta-adrenoreceptors b-receptors OH H HO N aaa HO Isoproterenol H OH H HO N aa HO Epinephrine H OH HO NH2 a HO Norepinephrine 5  Towards antagonism OH OH OH H H H HO N Cl N N HO Cl Isoprenaline Dichloroisoprenaline Pronethalol partial agonist partial agonist Catechol not required for antagonist Extra aromatic ring provide van der Waals / hydrophobic / pi-stacking opportunities – partial agonists – - weakly activate receptors – - block natural messenger 6  Partial agonist to antagonist (S) OH O N H H OH N OH H X N OH H Pronethalol Various analogues N synthesised and evaluated (S) partial agonist O Propranolol Spacer introduced - chain extension strategy antagonist Substituent is positioned at a different part of the ring 10-20 times greater antagonist activity Used clinically as a racemate S-Enantiomer is the active enantiomer Aryloxypropanolamine structure Activates β1 and β2 adrenoceptors 7  Improving antagonist activity Ring isostere opportunities Bulk secondary amine for greater β2 adrenoceptors selectivity O N O N H O N H OH O H OH OH N N N N S H Timolol O N O N H H OH OH O O Betaxolol Levobunolol 8  Timolol bound to b2 Adrenergic receptor 9 PDB 3d4s see video https://youtu.be/gG1-yfq5cx0 Selected molecular interactions of Timolol bound to b2 Adrenergic receptor Thr118 H O H Asn312 N N S Phe290 H H N O O O N H 3C NH2 H 3C O H 3C O O H Phe193 Asp113 H N Asn293 O 10 Interactions of Timolol bound to b2 Adrenergic receptor 11  Mode of action - Prostaglandins ↑ uveoscleral outflow to ↓ IOP Human prostaglandin F2a receptor agonists HO OH O HO HO H PGF2a Sites of structural variation O CH3 leading to O CH3 HO latanoprost HO OH 12  Structure activity relationship O O CH3 O CH3 N CH3 HO O CH3 O CH3 HO H HO F F O O HO HO OH F HO F F OH Bimatoprost Travoprost Tafluprost All have pro-drug functionality All maintain tetrasubstituted ring, Double bond variations Aromatic substituent on lower chain See also: Stjernschantz JW. From PGF2α-isopropyl ester to latanoprost: A review of the development of Xalatan. Investigative Ophthalmology and Visual Science 2001; 42: 1134-1145. 13 Latanoprostene bunod 14  a2 Adrenergic agonists for glaucoma Br Brimonidine and apraclonidine N H N H N Structurally related N N Brimonidine Brimonidine has >1000-fold selectivity for Cl H H a2 -receptors vs. N N N Clonidine or apraclonidine H 2 N Cl Apraclonidine Stimulation of a2-adrenoreceptors in the eye reduce production of aqueous humor and enhances outflow of aqueous humor 15  Cholinergics and glaucoma Acetylcholine is the endogenous cholinergic agonist Pilocarpine, Carbachol – cholinergic agonists O H 3C HO H3C CH CH3 N 3 N N CH H 3C O CH3 3 CH3 H3C O Acetylcholine N Nicotine Muscarine CH3 CH3 O H 3C CH3 O N N H 2N O CH3 O N Carbachol Pilocarpine 16  Acetylcholine hydrolysis Water / acid / base or enzyme-mediated H 3C Acetylcholine esterase H 3C O Water O CH3 + CH3 N N H 3C O CH3 H 3C OH HO CH3 Acetic acid Choline 17 Hydrolysis Of Acetylcholine Catalyzed By Acetylcholinesterase 18  Probing structure-activity relationship of acetylcholine Many analogues synthesized to: Enhance stability Improve selectivity – Varied many structural features – Few successes O H 3C CH3 N H 3C O CH3 19  Alternative to steric modifications Carbachol is more stable to hydrolysis O H 3C CH3 N O H 3C H 2N O CH3 CH3 N H 3C O CH3 O- H 3C Nucleophilic attack CH3 N H 2N O CH3 Less susceptible Structurally similar size to acetylcholine – functions as cholinergic agonist 20  Pilocarpine Isolated from Pilocarpus jaborandi Muscarinic agonist (M3) Susceptible to (i) hydrolysis of lactone, (ii) epimerization of carbon atom next to carbonyl CH3 CH3 CH3 CH3 CH3 CH3 Hydrolysis Epimerisation O N N O N O HO N O N O N OH 21  Carbonic anhydrase inhibitors Mode of action: ↓ aqueous humor secretion Carbonic Anhydrase CO2 + H2O HCO3- + H+ O O C H O H O O O- CH3 CH3 Zn2+ Zn2+ O His His His His HN S His His O H 2O S HCO3 - H H H H S O O O N O Inhibition Zn2+ Zn2+ Zn2+ His His His His His His His His His 22 See also: Nature Reviews Drug Discovery 2008, 7, 168-181 Dorzolamide bound to carbonic anhydrase PDB 4m2u see video https://youtu.be/gG1-yfq5cx0 23  Selected molecular interactions of dorzolamide bound to carbonic anhydrase Trp5 His64 H NH N Phe131 N H H NH Gln92 CH3 CH3 N H Thr200 O O O Val121 H HN S O S Leu198 O H S O H N N O Thr199 Zn2+ N N HN His96 N NH His94 NH His119 PDB 4m2u 24 Dorzolamide bound to carbonic anhydrase 25 Structure activity relationship H HN CH3 H HN CH3 H N H N S S O O S O O S N O S CH3 S O O O O Dorzolamide Brinzolamide 26  Example question 1 Which structure best represents a topical carbonic anhydrase inhibitor? H H CH3 CH3 H O N O N O N O N O CH3 H H H N O S O S O S O S O S H A Structure 4 S S S S S O O O O NH O S B Structure 2 O S N NH O S N NH O S N NH O S O H 3C H 3C H 3C H 3C H 3C C Structure 1 H 3C Structure4 D Structure 3 O O O O E Structure 5 Structure1 Structure2 Structure3 Structure5 27  Example question 2 Which amino acid is most likely involved in Pi-Pi stacking interactions? Thr118 H O H A Phe193 Asn312 N N S Phe290 H N B Asn312 O H O O C Asn293 N H 3C NH2 D Thr118 H 3C O O H 3C H O E Asp113 Asp113 H N Phe193 Asn293 F Phe290 O 28