Lead Optimization Lecture Notes (Pharm D Program 2023/2024)

Pharm PharmDDProgram Program (2023/2024) (2023/2024) (PC 710) Lecture No. (3) Lead Optimization...

Pharm PharmDDProgram Program (2023/2024) (2023/2024) (PC 710) Lecture No. (3) Lead Optimization By Dr. Abdelrahman Shalabi Lecturer of Medicinal Chemistry 12 October 2024 www.su.edu.eg 1  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s Aim Lead optimization strategies 12 October 2024 www.su.edu.eg 2  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s Competencies 1. Utilize information from basic science to handle, identify, extract, design, prepare, analyze, and assure quality of synthetic/natural pharmaceutical raw materials and finished products 1. Retrieve basic scientific drug information from different resources to solve problems related to human health and health systems 12 October 2024 www.su.edu.eg 3  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s Contents 1. Variation of substituents 2. Extension of structure 3. Chain extension/contraction 4. Ring expansion/contraction 5. Ring variation 6. Simplification/rigidification of structure 12 October 2024 www.su.edu.eg 4  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Target oriented drug design Target oriented drug design is to modify the lead compound such that it interacts more effectively & selectively with its target in the body Development of a novel drug from natural sources might follow the following pattern: 1) Screening of natural compounds for biological activity. 2) Isolation and purification of the active principle (using chromatographic techniques). 3) Determination of structure (using NMR, IR, mass spectroscopy and x-ray crystallography) 4) Structure activity relationships (SARs) 5) Design and synthesis of novel analogues. 12 October 2024 www.su.edu.eg 5  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Drug Optimization Drug-target interactions Access to the target 12 October 2024 www.su.edu.eg 6  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Optimizing target interactions Strategies of developing drugs Variation of Extension of substituents the structure Chain Ring extension / contraction expansion / contraction Ring Molecular Isosteres Modelling variations Simplification Design by Rigidification of structure NMR of structure 12 October 2024 www.su.edu.eg 7  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Aim : to optimize the activity Biological activity may depend not only on how the compound will interact with its receptor, but also on a whole range of physical features such as basicity, lipophilicity, electronic distribution, and size. 12 October 2024 www.su.edu.eg 8  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Alkyl substituents Large alkyl group may confer the selectivity 12 October 2024 www.su.edu.eg 9  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 10  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 11  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Aromatic substitutions A favorite approach for aromatic compounds is to vary the substitution pattern. This may give increased activity if the relevant binding groups are not already in the ideal positions for bonding 12 October 2024 www.su.edu.eg 12  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Electronic effects may also be involved e.g an electron withdrawing nitro group will affect the basicity of an aromatic amine more significantly if it is in the para position rather than the meta position. At p-position, the amine is weaker base 12 October 2024 www.su.edu.eg 13  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 14  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 15  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 16  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 17  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Replacement of an aromatic ring in adrenaline with a naphthalene ring system (pronethalol). This resulted in a compound which was able to distinguish between two similar receptors, the alpha and beta receptors for adrenaline. 12 October 2024 www.su.edu.eg 18  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Me too drug Non Steroidal Anti-inflammatory Drugs 12 October 2024 www.su.edu.eg 19  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Increase the selectivity Antifungal Non selective Selective to fungi 12 October 2024 www.su.edu.eg 20  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Increase binding interactions Antiviral agents 12 October 2024 www.su.edu.eg 21  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Increase binding interactions 12 October 2024 www.su.edu.eg 22  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 23  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 24  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Drugs containing asymmetric center (chiral drugs) 2-enantiomer Lower Cholesterol level 2nd generation Agonist & antagonist Of 5-HT1A 12 October 2024 www.su.edu.eg 25  Pharm PharmDDProgram Program (2023/2024) (2023/2024) How to decrease asymmetric centers 12 October 2024 www.su.edu.eg 26  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 27  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 28  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 29  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 30  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Conformational restriction 1) By simple introduction of a methyl group which sterically restricts free bond rotation. 2) By use of intramolecular hydrogen bonds. 3) By introduction of unsaturation which fixes the relative positions of the terminal & geminal substituents due to non- rotability of double bond. 4) By cyclization which fixes the relative position of the substituents either exocyclic or within the ring. 12 October 2024 www.su.edu.eg 31  Pharm PharmDDProgram Program (2023/2024) (2023/2024) By conformational restriction we expect to achieve: Increase in receptor / enzyme selectivity Increase in receptor / enzyme affinity Identification of pharmacophore Reduce intrinsic activity of agonist 12 October 2024 www.su.edu.eg 32  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Increase in receptor / enzyme selectivity 5-CT : 5-HT1A > 5-HT1D BRL56905 : 5-HT1D > 5-HT1A 5-Carboxamidotryptamine 12 October 2024 www.su.edu.eg 33  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Increase in receptor / enzyme affinity Desmethyl compound Capoten Relative potency = 1 Relative potency = 10 12 October 2024 www.su.edu.eg 34  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Identification of pharmacophore It is the form that has the correct spatial arrangement of all binding groups of drug molecules for binding with the corresponding binding sites on the receptors. i.e it is the spatial arrangement of the functionalities of a molecule which interact with the receptor & can take into account , sterically allowed & excluded volumes. The pharmacophore is the relative position of the important groups and ignores the molecular skeleton which holds them in 12 October 2024 www.su.edu.eg 35  Pharm PharmDDProgram Program (2023/2024) (2023/2024) 12 October 2024 www.su.edu.eg 36  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Reduce intrinsic activity of agonist Within a series of conformationaly restricted agonists small differences in the relative orientations of the functionalities may not affect binding but may affect the efficiency of activating the receptor e.g a series of acetylcholine mimetics from the muscarinic agonist group based on oxadiazole substituted azabicycles. 12 October 2024 www.su.edu.eg 37  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Intrinsic activity : 130 5 Intrinsic activity : 360 84 R= 12 October 2024 www.su.edu.eg 38  Pharm PharmDDProgram Program (2023/2024) (2023/2024) Lecture’s References Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th Ed.; Beale, J. M., Block, J. H., Eds.; Lippincott Williams & Wilkins: Philadelphia, 2011. Williams, D. A. Foye's Principles of Medicinal Chemistry. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2013 Patrick, G. An Introduction to Medicinal Chemistry. 6th ed. Oxford: Oxford University Press; 2017. 12 October 2024 www.su.edu.eg 39