Medicinal Chemistry, Day 1 PDF

Developing New Pharmaceutical Identify an assay → Identify a library or design compound → Assay Compounds → Identify lead compound structure → Optimize PK/PD properties → Clinical trials ​ Basic Science: Do we have a method that will cure the disease? ○​ Identify or develop an...

Developing New Pharmaceutical Identify an assay → Identify a library or design compound → Assay Compounds → Identify lead compound structure → Optimize PK/PD properties → Clinical trials ​ Basic Science: Do we have a method that will cure the disease? ○​ Identify or develop an assay (method for testing drug activity) ​ Assay must have the ability to bind to a target biomolecule (enzyme/receptor) AND produce an effect ​ Discovery of Lead Compounds: How do we know what compounds to test? ○​ Compounds can come from… ​ Rational design and synthesis / Library of compounds ○​ Assay compounds ​ Lead compounds are compounds that perform best in the assay ​ Lead Optimization: ○​ Optimize PK/PD properties of the lead ​ Clinical Trials Identifying a Lead Compound Forward Pharmacology (aka Phenotypic Approach) Reverse Pharmacology (aka Genotypic Approach) ​ Effect of the test compound on a whole organism is known ​ Effect of the test compound on a whole organism is NOT early in the discovery process known early in the discovery process ○​ Living organism used ​ Identity of drug mechanism or target is known ​ Identity of drug mechanism or target is NOT known ○​ NEED for a known drug mechanism or target is ○​ NEED for a known drug mechanism or target is NOT REQUIRED Phenotypic vs. REQUIRED ○​ Chance of finding a new drug mechanism or target Genotypic ○​ Chance of finding a new drug mechanism or target is LOWER is HIGHER ○​ Likelihood of binding multiple targets is LOWER ○​ Likelihood of binding multiple targets is HIGHER ​ Amount of animal testing is LOWER ​ Amount of animal testing is HIGHER ​ LESS compound is needed → LESS expensive ​ MORE compound is needed → MORE expensive ​ HIGHER assay throughput ​ LOWER assay throughout ○​ High assay throughput: High rate at which compounds can be tested (assayed)  A compound library is a collection of molecules having diverse chemical structures. Goal is to find a drug lead that will bind the desire target or have the desired biological effect in an assay Preselected Compound Library Natural Compound Library Compound Library Advantages ​ Known chemical structures that are ​ Chemically diverse, readily available, and pre-screened generally inexpensive Disadvantages ​ Limited structural diversity and expensive ​ Active compounds can be difficult to isolate ​ May not have good drug properties Lead compounds from natural products usually derive from secondary metabolites ​ Primary metabolites → REQUIRED: ○​ Metabolic intermediates essential to growth and life Natural ​ Secondary metabolites → Supplemental: Products ○​ Compounds produced by organisms to improve chances of survive by helping them interact How can lead compounds be found from natural products? ​ Ethnobotany: Field that studies the ways human cultures use plants for medical and other purposes ○​ Ethnobotany helps narrow down the number of species that need to be studied to find a drug lead ​ Approved Drugs from Natural Products: ○​ Morphine, Lovastatin, Penicillin G Rational Drug Design is a modern method that allows accurate 3D modeling of proteins and their ligands. This has made it possible to identify drug leads in silica (by computer) Structure-Based Drug Discovery Ligand-Based Drug Discovery Rational Drug ​ Structure of the target protein is used to identify a drug ​ Known ligand for the target protein is modified in an Design that will bind the protein attempt to create a drug with improved binding ○​ Virtual Screening: Computer library of existing ○​ A chemical analog: making small changes to chemical structures are fit into a protein model improve the ligand protein binding ○​ De Novo Design: Making of new compounds from ​ No protein structure required scratch to “custom-fit” the protein Approved Drugs created by Rational Drug Design: Celecoxib and Imatinib  Pharmacophores of Drug Classes Opioid Barbiturate Adrenergic Agonist Benzodiazepine Quinolone Angiotensin Receptor Blocker Penicillin Cephalosporin Proton Pump Inhibitor Statin NSAID  Structure Activity Relationships (SAR) and Uses Structure Activity Relationship: How changing structure changes function ​ Functional Groups are HYDROPHILIC (aka LIPOPHOBIC) if it has a O or N ○​ Carboxylic acid, ester, amide, nitrile, aldehyde, ketone, alcohol, thiol, amine, ether ​ Functional Groups are HYDROPHOBIC (aka LIPOPHILIC) if it does not have an O or N ○​ Sulfide, halide, alkyne, alkene, alkane ○​ Has longer C chains Lipophilicity ​ Greater lipophilicity = quicker onset = shorter duration of action ○​ Lipophilic compounds have shorter duration of action because it can be rapidly absorbed but also rapidly diffused out ​ Modifications of 3-OH → Analgesic potency will DECREASE Opioid ​ Modifications of 6-OH → Analgesic potency will INCREASE Analgesic ​ Modifications at piperidine: ○​ If at 14, -OH is added → Analgesic potency will INCREASE ○​ If N-CH3 is changed to N-H → Analgesic potency will DECREASE ○​ If N-CH3 becomes N-R (R=3-5 carbon chains) → Compound will become an ANTAGONIST ​ Ex. methylnaltrexone Benzodiazepine Penicillin The R must be an aromatic ring… but just aromatic containing. Cis vs. Trans E-isomer is more potent ɑ1 Receptor β2 Receptor ​ Contraction of smooth muscle ​ Bronchodilation ​ Determining Selectivity: ​ Determining Selectivity: ○​ OH at 3’ position favors alpha activity ○​ OH at 4’ position favors beta activity ○​ Small groups at R2 favors alpha selectivity ○​ Large groups at R2 favors beta selectivity ​ Smaller than ethyl ​ Ethyl or larger groups ○​ Small groups at R1 favors alpha selectivity ○​ Large groups at R1 favors beta selectivity ​ Smaller than isopropyl ​ Larger than isopropyl Adrenergic Agonist What if there is -OH at both R3 and R4? 3’-4’-(-OH at both R3 AND R4) diOH susceptible to metabolism by COMT  Opioid Analgesic ​ Modifications of 3-OH → Analgesic potency will DECREASE ​ Modifications of 6-OH → Analgesic potency will INCREASE ​ Modifications at piperidine: ○​ If at 14, -OH is added → Analgesic potency will INCREASE ○​ If N-CH3 is changed to N-H → Analgesic potency will DECREASE ○​ If N-CH3 becomes N-R (R=3-5 carbon chains) → Compound will become an ANTAGONIST ​ Ex. methylnaltrexone ​ Opioid-Induced constipation can be treated using methylnaltrexone