Intro to Med Chem - Drug Pharmacophores.pptx

Drug Pharmacophores PHA3129 – Introduction to Medicinal Chemistry CHRIS BRACKETT PH.D. Overview/Learning Objectives Understand and identify pharmacophores for the selected classes of commonly encountered drugs What is a Pharmacophore? A pharmacophore is a structural motif of a drug class that is...

Drug Pharmacophores PHA3129 – Introduction to Medicinal Chemistry CHRIS BRACKETT PH.D. Overview/Learning Objectives Understand and identify pharmacophores for the selected classes of commonly encountered drugs What is a Pharmacophore? A pharmacophore is a structural motif of a drug class that is responsible for the biological activity of the drug IUPAC definition: ◦ ‘An ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response A typical pharmacophore will incorporate some combination of aliphatic or aromatic rings, hydrogen bond donors/acceptors, cations/anions, etc… H N O H S N O O Penicilli nG OH Common Pharmacophores Benzodiazepines Barbituates β-lactam antibiotics Quinolone antibiotics Beta blockers Statins Fibrates Calcium channel blockers (dihydropyridine) ACE inhibitors Angiotensin II Receptor Blockers (ARBs) Anti-inflammatory steroids Beta agonists NSAIDs Antihistamines Proton Pump Inhibitors Sulfonylureas SGLT2 Inhibitors Benzodiazepines Benzodiazepines are class of molecules used to treat a variety of anxiety disorders They act on the GABA (γaminobutyric acid) receptor, and enhance its effects ◦ Positive, allosteric modulators of the GABA receptor ◦ Has sedative, anti-anxiety, anticonvulsant, and muscle relaxant properties Cartoon view of the GABA receptor Benzodiazepine Pharmacophore Extensive research on the first benzodiazepine pharmacophore, 5-phenyl-1,4-benzodiazepine-2one has revealed certain key structure-activity relationships: ◦ Replacing ring ‘A’ with other heterocycles generally decreased the activity ◦ Substituents at positions other than R7 on ring A also led to decreased activity ◦ Electron-withdrawing groups at R7 greatly increased activity R1 1 N 9 8 R7 7 A 2 B 3 N4 5 6 1’ 6’ 5’ O 2’ C 4’ 3’ X R3 Benzodiazepine Pharmacophore Substitution at the amide nitrogen (R1) is not necessary, nor is the carbonyl at position 2 Ring C is not required for binding in vitro, but contributes favorable hydrophobic interactions ◦ Ortho substituents disrupt planarity, which leads to increased activity R1 1 N 9 8 R7 7 A 2 B 3 N4 5 6 1’ 6’ 5’ O 2’ C 4’ 3’ X R3 Benzodiazepine Pharmacophore In addition, several benzodiazepines have been discovered which contain an additional ring R R1 N O N Y N R3 R7 N Cl X N X Benzodiazepine Pharmacophore Commonly prescribed benzodiazepines: N N Cl H N O N O2N O N O N Cl N N N Cl N Cl Diazepa m (Valium ) Clonazep am (Klonopin ) Temazep am (Restoril) Alprazola m (Xanax) Barbiturates Barbiturates are another class of drugs that act as positive allosteric modulators of the GABA receptor ◦ Their binding site is distinct from the benzodiazepine binding site ◦ Can have synergistic effects when co-administered with benzodiazepines They produce the same types of effects as benzodiazepines, and have been largely replaced in the treatment of anxiety disorders, but are still used in general anesthesia Barbiturate Pharmacophore The drug class derives both their name and general structure from barbituric acid. Commonly encountered barbiturates: O HN O O NH O HN O O O NH O HN O NH O HN O S NH O HN O NH O Barbituri c acid Amobarbit al Pentobarbi tal Phenobarb ital Thiopental β-Lactam Antibiotics β-lactam antibiotics are the most widely prescribed class of antibiotics ◦ Several different classes of βlactam antibiotics with slightly different pharmacophores All β-lactam antibiotics have the same mechanism of action ◦ Inhibition of cell-wall crosslinking through binding and inhibiting penicillin-binding proteins (PBPs) β-Lactam Pharmacophores R H N O NH O H S N O Penicilli ns OH R2 R3 N O β-lactam R2 HO H H H N O S N O O O OH Carbapene ms O R1 OH Cephalospori ns β-Lactam Pharmacophores Penicillins were the first class of β-lactam antibiotics to be described ◦ The original penicillins exhibited poor pharmacological properties (susceptibility to acid hydrolysis), and narrow spectrum range (only N Gram-positive bacteria) O ◦ Semisynthetic efforts lead to more stable and orally available N O penicillins O R H N O H NH NH2 H N S O N O O OH H S HO N O H N O H H N S O N Benzylpenicill in OH O Amoxicillin S N O O O H OH O Piperacillin OH β-Lactam Pharmacophores Cephalosporins were the second class of β-lactam antibiotics to be described ◦ Has been the subject of extensive medicinal chemistry efforts ◦ There are five generations of cephalosporins. Initial generations showed increased activity against Gram-negative bacteria with reduced activity against Gram-positive bacteria. Fourth and fifth generations are O considered extended broad spectrum antibiotics OH O R2 H N O H N O O NH2 H N S HO R1 OH O H O H N S O N O O O O N OH Cefadroxil (First) H S O N NH2 O S N N H2N N H N O H S N N N O O OH Cefuroxime (Second) O NH2 NH2O OH Ceftolozane (Fifth) NH NH β-Lactam Pharmacophores Carbepenams were the last class of β-lactam antibiotics introduced. ◦ Only class without a sulfur in the ring fused to the β-lactam ◦ Tend to have more broad spectrum activity and are not as susceptible to β-lactamase hydrolysis H N NH R2 HO H H HO H H R3 N O HN S N OH O OH Imipenem O H N HN HO H H S H N O O O HO H H N S H N O O OH Meropenem O OH Ertapenem OH O O Quinolone Antibiotics Another widely used class of antibiotics are quinolone antibiotics Quinolones act by inhibiting DNA gyrase ◦ By inhibiting DNA gyrase, quinolones prevent bacterial DNA replication Quinolones are active against both Gram-positive and Gram-negative bacteria Most commonly prescribed quinolones contain a fluorine, so they are also referred to as fluoroquinolones Quinolone Pharmacophore While not technically a quinolone, nalidixic acid is considered the first quinolone antibiotic, and served as the starting point for medicinal chemistry studies O O OH N N Nalidixic acid Quinolone Pharmacophore While not technically a quinolone, nalidixic acid is considered the first quinolone antibiotic, and served as the starting point for medicinal chemistry studies Quinolone Pharmacophore Commonly encountered quinolones/fluoroquinolones: O F N O O F OH N HN F OH N N O O N H F OH N O O O N O N N OH N O NH H NH2 Ciproflox acin Levofloxa cin Moxiflox acin O Gemifloxa cin Beta Blockers Beta blockers are a class of drugs named for their mode of action: ◦ They block/antagonize the β-adrenergic receptors, found predominantly in cardiac tissue, leading to vasodilation ◦ Beta blockers are indicated for a variety of conditions, but are predominantly used to treat arrhythmias and high blood pressure There are several classes of adrenergic receptors, which are classified by their response to norepinephrine, epinephrine, or isoproterenol OH by isoproterenol, which OH ◦ Only β-adrenergicOH receptors are activated serves as H H HO 2 N HO the structural basis forNH these drugs N HO HO Norepinephrine HO Epinephrine HO Isoproterenol Beta Blocker Pharmacophore Subsequent medicinal chemistry efforts starting from the βadrenergic agonist, isoproterenol, developed propranolol ◦ First clinically successful beta blocker ◦ Portion in red is the pharmacophore employed by all future beta blockers OH HO H N O OH N H HO Isoproterenol Propranolol Beta Blocker Pharmacophore First generation beta blockers were not selective towards the β1 adrenergic receptor ◦ Also inhibits β2 adrenergic receptors, which leads to bronchoconstriction Second generation beta blockers are selective for the β1 adrenergic receptor, and have less off target effects O OH N H Propranolol (Nonselective) O OH O N H Metoprolol (β1 selective) Beta Blocker Pharmacophore β1 selective Nonselective O OH O N H OH Propranolol N H Metoprolol O O OH O HO OH N H N H N H O Carvedilol O O OH N H N H O OH HO Atenolol Nadolol Bisoprolol O NH2 O O Statins Statins are a class of drugs prescribed to help lower blood cholesterol They act through inhibition of HMG-CoA reductase ◦ HMG-CoA reductase catalyzes the rate determining step in the production of cholesterol Statin Pharmacophore Lovastatin was the first FDA approved HMG CoA reductase inhibitor Lovastatin is a prodrug, which when activated, acts as a structural mimic of the HMG CoA reductase intermediate O OH ◦ The affinity for HMG CoA reductase of the active form of lovastatin is ~20000x greater HO than HMG O CoA HO O O In vivo O H Lovastatin HO O O H Active metabolite Statin Pharmacophore Medicinal chemistry efforts focused on simplifying the bicyclic core to make synthesis easier O HO O HO O O H O OH HO HO HO F F N H HO O NH N N N Simvastatin OH HO HO O O O O OH Pravastatin Atorvastatin O S O Rosuvastatin Fibrates Fibrates are a class of drugs prescribed to treat metabolic disorders, primarily hypertriglyceridemia and hypercholesterolemia Fibrates activate peroxisome proliferator-activated receptor α (PPARα) ◦ PPARα is a ligand-activated nuclear receptor that regulates numerous genes, including those associated with both glucose and fatty acid metabolism ◦ Activation of PPARα causes an upregulation of fatty acid oxidation, lipoprotein lipase enzyme, and increases Fibrate Pharmacophore Clofibrate was the first approved PPARα agonist approved for treatment ◦ Clofibrate was discontinued in 2002, in part due to clinical trials showing an increase in mortality despite successfully lowering cholesterol Clofibrate served as the starting point for development of safer O O and more effective drugs O O O In vivo OH Cl Cl Clofibrate Active metabolite Fibrate Pharmacophore Commonly prescribed fibrates: O O Cl O O O O O O OH N H Cl O Fenofibrate Gemfibrozil Bezafibrate OH Calcium Channel Blockers Ca2+, along with Na+ and K+, are key ions involved in the excitation-contraction process in the cardiovascular system ◦ Influx of Ca2+ in to the cell is a key step in the cardiac action potential Calcium channel blockage results in reduced cardiac output ◦ Lowered heartrate ◦ Lowered blood pressure Several different classes of CCBs exist, however the dihydropyridine class is the most widely used Dihydropyridine CCB Pharmacophore H H O R3 N Pyridine N H R4 O O O R2 N H R5 R6 Dihydropyridine Calcium channel blocker pharmacophore Basic SAR trends for dihydropyridine calcium channel blockers: ◦ Substitution at the nitrogen abolishes activity ◦ R4 is typically a phenyl ring with an ortho/meta substitution. Para substitution decreases activity ◦ If the esters are not symmetrically substituted (R3 ≠ R5), drugs will have more selectivity towards specific blood vessels Dihydropyridine CCB Pharmacophore Commonly prescribed dihydropyridine calcium channel blockers: NO2 O2N O Cl O O O O O2N O O O O O N H N H Nifedipine Amlodipine O NH2 O O O O O O N H N H Nisoldipine Nimodipine O ACE Inhibitors Angiotensin-converting enzyme (ACE) inhibitors act on the renin-angiotensin pathway by blocking the conversion of angiotensin I to angiotensin II, which is catalyzed by ACE ◦ Angiotensin is an octapeptide that is a powerful vasoconstrictor ACE inhibitors are used to treat high blood pressure and heart failure ACE Inhibitor Pharmacophore The first ACE inhibitor discovered was the nonapeptide teprotide, which was isolated from the venom of the Bothrops jararaca snake ◦ It has the amino acid sequence Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro ◦ Teprotide served as structural inspiration for captopril, the first clinically approved ACE inhibitor O H N HN H N O O NH O O N HN O O NH H2N NH Teprotide O NH2 O O N N HN OH O O HS N Captopril OH ACE Inhibitor Pharmacophore Characteristics of commonly prescribed ACE inhibitors: O HO ◦ Proline portion of the molecule fills a hydrophobic pocket, while amide and carboxylic acid form key hydrogen bonds ◦ Drug must also contain some functional group that can chelate Zn2+ Benzapril, enalapril, and ramipril are all prodrugs H N O O OH N O O H N O O OH N Enalapril NH2 Lisinopril O O H N OH O O O N O H N O OH N H Benzapril O H Ramipril Angiotensin II Receptor Blockers In addition to inhibiting the reninangiotensin pathway through inhibition of angiotensin II production, another drug target is the angiotensin II receptor ◦ Angiotensin II receptor antagonists (ARBs) block angiotensin II receptor type 1 Used primarily to treat: ◦ Hypertension ◦ Diabetic nephropathy ◦ Congestive heart failure ARBs Pharmacophore S-8308 was the first nonpeptide antagonist of the angiotensin II receptor discovered ◦ It mimicked several key interactions between angiotensin II and its receptor ◦ S-8308 was the starting point for medicinal chemistry efforts towards orally bioavailable ARBs ARBs Pharmacophore Commonly prescribed angiotensin II receptor antagonists: OH O N N Cl N N O O N N N Losartan N O OH HN N N N N HN N N N O Candesartan cilexetil O O O O N N NH N Valsartan HN N N N Ibesartan HN N N N N Telmisartan N Anti-Inflammatory Steroids Anti-inflammatory steroids, also referred to as corticosteroids, are the most commonly prescribed class of antiinflammatory drugs Corticosteroids exert their effect through activation of the glucocorticoid receptor, which has two primary effects: ◦ Increase in blood sugar ◦ Increased expression of antiinflammatory proteins, and decreased expression of proinflammatory pathways Used to treat a diverse array of conditions Kadmiel M, Cidlowski JA. Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci. Corticosteroid Pharmacophore Cortisol is the endogenous steroid hormone involved in glucocorticoid signaling, and serves as a basis for medicinal chemistry efforts ◦ Cortisol also activates the mineralocorticoid receptor, which mediates electrolyte and fluid balance. ◦ Medicinal chemistry efforts focused on enhancing glucocorticoid receptor selectivity Cortisol is also known as hydrocortisone ◦ Cortisol is used when describing its actions as a hormone, hydrocortisone is used when used as a medication O HO OH OH H H H O Cortisol Corticosteroid Pharmacophore Commonly prescribed corticosteroids: OH OH O OH OH O H H H O O OH CH3 HO F O HO O H H H O Prednisone O HO O Dexamethasone Budesonide O O O O O HO Cl O O HO H CH3 H H Belcomethasone O F O O S F CH3 H FFluticasone propionate Beta Agonists Whereas β-adrenergic receptor antagonists are used for their ability reduce cardiac output, β-adrenergic receptor agonists are used as a first line treatment for asthma ◦ β1 adrenergic receptors are primarily located in cardiac tissue ◦ β2 adrenergic receptors are primarily located in lung tissue Much like with β-adrenergic receptor antagonists, isoproterenol served as a starting point for the development of β-adrenergic receptor agonists Beta Agonists Pharmacophore From the isoproterenol starting point, the development of beta agonists focused on two primary modifications: 1. Steric bulk on the nitrogen ◦ Switching the methyl group of epinephrine to an isopropyl group (isoproterenol) greatly reduces affinity for α receptor ◦ Also, steric bulk shows preferential selectivity for β2 receptor OH HO HO H N Epinephrine OH HO HO H N Isoproteren ol β2 selective agonists Beta Agonists Pharmacophore From the isoproterenol starting point, the development of beta agonists focused on two primary modifications: 2. Modifying the catechol backbone ◦ Shifting one of the phenol groups to another position or changing the identity of the ring can also increase selectivity ◦ Also, prevents metabolism by catechol o-methyl transferase (COMT) HO HO R R HO R HO OH R O HO OH HN O R R HO HO HN HN O O Beta Agonists Pharmacophore Commonly encountered beta agonists: OH HO OH H N HO H N HO HO Albuterol/ Salbutamol OH Salmeterol OH H N H N HO HO HN O Formoterol O HN OIndacaterol O NSAIDs Nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting the production of prostaglandins and other down stream inflammatory molecules by inhibiting cyclooxygenases 1 and 2 (COX-1 and COX-2) ◦ Block the conversion of arachidonic acid to PGH 2 O OH OH COX-1/2 O O OH Arachidonic acid O PG H2 NSAIDs Pharmacophore There are several class of NSAIDs, however, the largest class of NSAIDs are the arylalkanoic acids Arylalkanoic acid NSAIDs are divided in to two subclasses: ◦ R = H, aryl acetic acid NSAIDs, “-fenacs” ◦ R = CH3, aryl propionic acid NSAIDs, “profens” ◦ The extra methyl group adds a stereocenter to the drug, (S)enantiomer is active R OH Ar O Ar = aromatic ring R = H, CH3 NSAIDs Pharmacophores Commonly encountered NSAIDs: O Cl O OH O OH H N OH N O O Cl Diclofen ac Ibuprofen Cl Indometha cin OH OH O O O Naproxe n F Flurbipro fen Antihistamines The class of drugs referred to as antihistamines are those that block the histamine H1 receptor ◦ There are four classes of histamine receptors ◦ The H1 receptor is expressed in cells associated with inflammation and the immune system H1 receptor antagonists relieve allergy symptoms ◦ First generation antihistamines also cross the blood-brain barrier which leads to drowsiness NH2 N N H Histamine Antihistamine Pharmacophore Antihistamine Pharmacophore Antihistamine Pharmacophore Commonly used antihistamines: First Generation O Cl N N O N N N Diphenhydramine Doxylamine Hydroxyzine OH O Cl O OH N Second Generation HO HO N N Fexofenadine Cetirizine OH O O Proton Pump Inhibitors Proton pump inhibitors (PPIs) are a class of drugs that act to reduce the production of stomach acid through irreversible inhibition of the H+/K+ ATPase proton pump PPIs are used to treat: ◦ Peptic ulcer disease ◦ H. pylori infection ◦ Gastroesophageal reflux disease (GERD) ◦ Zollinger-Ellison syndrome Proton Pump Inhibitor Pharmacophore All proton pump inhibitors are prodrugs which are weakly basic and are activated in the highly acidic environment of the stomach H N R1 O S N N R4 R2 O R3 Proton Pump Inhibitor Pharmacophore Commonly encountered proton pump inhibitors: H N O O S H N N N O S N N O Omeprazole Lansoprazole O F F F H N F F O O S H N N N N N Pantoprazole O O S O Rabeprazole O O Sulfonylureas Sulfonylureas are a class of drugs used to treat type 2 diabetes ◦ They stimulate the release of insulin from the β cells of the pancreas Sulfonylureas block ATP-sensitive K+ channels, leading to depolarization of the cell and an influx of Ca2+ ◦ This causes insulin containing granules to be trafficked to the cell membrane and their release out of the cell Sulfonylurea Pharmacophore The first sulfonylureas were discovered during research in to sulfonamide antibiotics There are two generations of sulfonylureas: ◦ First generation sulfonylureas have largely been replaced by second generation drugs. ◦ Second generation drugs have shorter plasma half-lives, longer duration of action, and are more potent O O O R2 S N N H H R1 Sulfonylurea Pharmacophore Commonly encountered sulfonylureas: O O O N S N N H H First Generation Second Generation N N Tolazamide O O O S N N H H O O O O S N N H H Cl Chlorpropamide O O N N H Glipizide O O O S N N H H N H Glimepiride SGLT2 Inhibitors Sodium-glucose cotransporter 2 (SGLT2) is located in the kidneys and is important in glucose homeostasis ◦ SGLT2 will reabsorb all of the glucose from the renal tubules back in to the plasma ◦ When blood glucose levels become too high, SGLT2 can no longer reabsorb all of glucose and glucose will be excreted through the urine Inhibition of SGLT2 in diabetic patients increases the amount of glucose excreted in the urine SGLT2 Inhibitor Pharmacophore Phlorizin was the first discovered SGLT2 inhibitor, however, it is quickly degraded by β-glucosidases found in the GI tract ◦ Phlorizin served as the structural basis for the clinically successfully SGLT2 inhibitors HO HO HO OH HO O HO O OH OH O R2 HO OH O Ar R1 SGLT2 inhibitor pharmacophore Phlorizin OH SGLT2 Inhibitor Pharmacophore Commonly encountered SGLT2 inhibitors: HO HO HO HO O S HO F O HO OH OH Canagliflozin HO HO Cl O Empagliflozin HO HO O HO O S HO OH Cl O Dapagliflozin OH F Ipragliflozin O Review Be able to identify drugs by their pharmacophores ◦ Understand the mechanism of action for these classes of compounds