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The Organic Chemistry of Drug Design and Drug Action

Medicinal Chemistry. The science that deals with the discovery or design of new therapeutic agents and their development into useful medicines.It involves: Synthesis Structure-Activity Relationships (SAR) Receptor interactions Absorption, distribution, metabolism, and excretion (ADME) and toxic

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The Organic Chemistry of Drug Design and Drug Action

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    2. Medicinal Chemistry

    3. Medicinal Chemistry Folklore

    4. Discovery of New Drugs

    5. Drug Discovery One way to “discover” drugs

    7. Drug Discovery

    9. Clinical Trials

    10. Drug Discovery

    11. Drug Discovery Without a Lead

    15. Lead Discovery

    16. High-throughput Screens (HTS)

    17. Other Screening Approaches

    18. Lead Discovery Approaches

    21. Drug Discovery from Clinical Observations

    24. Rational Drug Design

    25. Example of Rational Drug Design

    26. Problems with Rational Approaches

    27. Lead Modification

    28. Identification of the Active Part of the Lead

    31. Example of Pharmacophore and Auxophore Identification

    38. Fentanyl and derivatives are the most potent opiates known. Is the ester group in carfentanil part of the pharmacophore?

    39. Functional Group Modification

    40. Structure-Activity Relationships (SARs)

    42. Example of SAR

    43. SAR General Structure of Antimicrobial Agents

    46. SAR for Paclitaxel

    48. Privileged Structures and Drug-like Molecules

    49. Drug-likeness

    51. Structural Modifications

    52. Types of Structural Modifications

    54. Chain Branching

    55. Ring-Chain Transformations

    57. Bioisosterism

    63. Changes in Activity by Bioisosterism

    65. Bioisosterism allows modification of physicochemical parameters

    66. Combinatorial Chemistry

    69. Peptide Libraries

    71. Split Synthesis of Most Active Hexapeptide for a ? Opioid Receptor

    73. Problems with Split Synthesis Approach

    74. Alternative Approach

    75. Encoding Combinatorial Libraries

    76. General Approach for Encoding Combinatorial Libraries Scheme 2.3

    77. Tag Molecules

    78. Identification of Active Bead

    79. Example of Encoding Peptide Libraries

    82. Nonpeptide Libraries Problems with Assaying Multiple Compounds Together

    83. Parallel Synthesis of Privileged Structure Library

    85. Solid-Phase Synthesis of a Natural Product-like Combinatorial Library

    86. SAR by NMR NMR approach to identify and optimize high-affinity ligands bound to proteins

    87. Example of SAR by NMR

    88. SAR by NMR What’s Really Involved?

    89. Combinatorial Lead Optimization Using Principles of SAR by NMR - no structural information needed

    90. SAR by MS

    91. Peptidomimetics

    93. Phenylalanine Peptidomimetics

    94. Conformationally-Restricted Peptides

    95. Secondary Structure Mimetics

    96. Scaffold Peptidomimetics

    98. Peptide Backbone Isosteres Peptide amide bond replaced with alternative groups

    99. Structure Modifications to Increase Oral Bioavailability

    101. Electronic Effects The Hammett Equation

    102. Hammett Equation

    103. Rate Constants

    104. Linear Free-Energy Relationship

    106. Lipophilicity Effects: Hansch Equation

    107. Fluid Mosaic Model of Membrane Drug must pass through various membranes to reach the site of action

    108. Measured Lipophilicities Model for transport of drug to site of action

    109. Relative potency of drug (log )

    110. Parabolic Relationship Between Potency (log ) and log P

    112. Effect of pH on log D

    113. Lipophilicity Substituent Constants p

    116. Example of Additivity of ? Constants Branching lowers log P or ? by 0.2/branch

    117. Computerization of Log P Values

    118. Effects of Ionization on Lipophilicity and Oral Bioavailability

    124. Actual pKa Values

    127. Other Properties that Influence Oral Bioavailability Lipinski’s Rule of 5

    128. Alternative to Lipinski’s Rule of Five Veber and co-workers

    129. Quantitative Structure-Activity Relationships

    130. QSAR

    131. Steric Effects: Taft Equation

    132. Correlation of Physicochemical Parameters (descriptors) with Biological Activity

    133. Hansch equation generalized:

    134. Topliss Operational Schemes - Lead Optimization

    135. Topliss Decision Tree

    138. Batch Selection Methods

    140. Cluster Analysis

    141. Computer-Based Methods of QSAR

    142. Comparative Molecular Field Analysis (CoMFA)

    143. Molecular Graphics

    151. Molecular Modeling in Lead Modification

    155. Epilogue

    156. Epilogue (cont’d)

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