Plants Examples with Historical Background in Medicinal Chemistry | CHEM 4000, Study notes of Chemistry

Download Plants Examples with Historical Background in Medicinal Chemistry | CHEM 4000 and more Study notes Chemistry in PDF only on Docsity! CHAPTER 1: HISTORICAL BACKGROUND Plant Examples  Ch’ang shang: roots of Dichroa febrifuga…treat fever in China  Ma huang: stems of Ephedra sinica…treat cough, asthma in China  Squill: bulb of Urginea maritimai…used as diuretic, cardiac tonic in Egypt  Autumn crocus: Colchicum autumnale…treat joint pain in Egypt  Ourari: vines of Chododendrum tomentosum…used in hunting as paralytic in S. America  Coca: leaves of Erythroxylon coca…used as euphoric in Inca  Opium poppy: Papaver somniferum…treat pain in Sumer, Egypt, Greece, China  White Willow: bark of Salix alba…treat inflammation in Greece, Sumer, Assyria, America  Common foxglove: preparation of Digitalis purpurea…”dropsy”  taxol: bark of Taxus brevifolia…treats tumors Isolation of Pure Compounds  important isolations o 1805: Serturner - morphine from poppy o 1820: Pelletier - colchicines from Autumn crocus o 1839: salicylic acid from White willow o 1855: Gaedcke - cocaine from Coca o 1885: Nagai - ephedrine from Ma huang  isolation of an alkaloid o powder the plant, extract w/benzene & Na2CO3 (amine in organic phase) o extract benzene w/dilute HCl (amine in aqueous phase, protonated) o extract aqueous layer w/CHCl3 & K2CO3 (amine in organic phase, free base) o evaporate CHCl3, recrystallize as oxalate salt Semi-Synthesis o common reaction: alcohol to acetate ester  morphine  heroin (more lipophilic, much more addictive)  salicylic acid  acetylsalicylic acid (aspirin) (less irritating to stomach) Structure Identification o advances in spectroscopy during 1900s o analog synthesis (advances in synthetic tech)  making complex natural products o advances in biochem  protein structure, DNA structure, allows for targeting o understanding of specific interaction with macromolecular target (mechanisms) o degradation of natural products into smaller pieces led to structure identification  morphine, burning and identifying from elemental analysis, long & tedious!  natural products include: codeine & thebaine o modern methods include NMR, IR, MS, x-ray (more efficient)  taxol, isolated from Taxus brevifolia Total Synthesis  from small, commercially available precursor  allows for preparation of analogs from various points in process  can be racemic or enantioselective (usually only one enantiomer is active)  ephedrine synthesis o Nagai achieved racemic mixture in 3 steps o Hildebrandt achieved enantiopure in 2 steps (enzymatic process!)  morphine synthesis is now far more efficient, achieving enantiopurity Mechanism of Action Work  Ehrlich introduced “side-chain” theory, explained toxin-antitoxin interactions o concept of “magic bullet” to target specific bacteria led to first synthetic drug! o side-chain theory developed into concept of receptor for poisons or drugs o first synthetic drug: salvarsan (treats syphilis), toxic but has antibacterial properties  Langley stated that the drug interacts with a “specific receptive substance” o observed antagonist action of atropine (speeds) and pilocarpine (slows)  pilocarpine: derived from Pilocarpus shrubs, muscarinic agonist  atropine: derived from Atropa belladonna, muscarinic AchR antagonist  Clark quantified drug action (dose response)  Ahlquist distinguished between α and β subtypes of adrenoceptor (different receptor types)  1970s: isolation of specific receptors Enzyme History  Kuhne proposed “enzyme” term to describe fermentation of sugar to alcohol  Buchner named “zymase” to be the enzyme responsible  Fischer propsed “lock and key” hypothesis to describe enzyme/substrate interaction  Phillips obtained first x-ray of lysozyme o x-ray structure collection is easier to perform on enzymes than receptors due to size Drug Discovery  begin with “hit” or “lead” identification  early lead sources o natural sources o natural ligands o compound libraries o literature o clinical observations  lead modification (to make a drug) o structure-activity relationships (SAR)…Which parts are important for binding? o modify lead to maintain pharmacophore, improve activity, reduce toxicity o increase/decrease side chains, use bioisosteres o modify the core structure  drugs from folk medicines o morphine  meperidine (Demerol) o cocaine  procaine (novocaine) o tubocurarine  pancuronium  ephedrine modification o analogs include: amphetamine, mathamphetamine, fenfluramine, methylphenidate (Ritalin) o act at adrenoceptor (mimic adrenaline aka epinephrine) CHAPTER 3: DRUG DISCOVERY-LEAD MODIFICATION reasons to perform lead modification  improve intrinsic activity o in vitro screening (IC50) tells you binding affinity to substrate (inhibitory concentration) o in vivo screening (ED50) tells you defined activity in animal model (effective dose)  improve pharmacokinetics (ADME studies) o absorption o distribution o metabolism o elimination  reduce toxicity o LD50 tells you lethal dose in 50% of animals tested o therapeutic index (LD50 / ED50) should be high, toxic only at high concentrations  allow for patentability  maintain pharmacophore throughout o 3-D arrangement of functional groups required for binding o usually has 3-4 contact points with target o remainder of molecule is “scaffold” o example: somatostatin  naturally occurring peptide hormone  analog synthesized by Merck  pharmacophore elements include: tryptophan (indole) and lysine (alkyl amine) side chains  non-peptide analog: substituted β-D-glucose  overlap of two essential side chains indicates promising drug potential o example: opioid pharmacophore  consists of a ring structure and N with 2 alkyl groups  is maintained throughout analogs of morphine  drugs include:  morphine  codeine  heroin  levorphanol?  pentacocine?  meperidine (Demerol)  Darvon  methadone  etorphine pharmacophore identification o determine relative importance of different functional groups in one congeneric series o important functional groups  H-bond donors (OH, SH, NH)  H-bond acceptors (C=O, NR3)  ionic groups (CO-2, R4N+)  aryl groups  alkyl chains o hypothesize on correspondence to other series or compounds or to binding site model o methods include: classical SAR and molecular modeling  classical SAR (structure-activity relationships)  identify compounds with known activity, compare and identify common structural features, so all new compounds should have those features  example: sulfanilamide antibacterials o 1935: discovered from azo dyes, lead: prontosil (red dye) o marketed sulfanilamide as elixir in ethylene glycol (“antifreeze”) o 1938: Food, Drug, and Cosmetic Act passed requiring proof of safety o act was modified in 1962 to include efficacy o pharmacophores include:  p-amine-aryl-sulfonamide  p-alkyl-aryl-sulfonylurea  bicyclic aryl sulfonamide  QSAR (quantitative SAR)  mathematical relationship between structure and bioactivity  biological properties are function of physicochemical parameters o electronic parameter  Hammett constant ()  tells you about e-withdrawing property of substituent  H = log (KX/KH), with subst. X and dissociation constant KH higher value indicates greater electron-withdrawal o lipophilicity  partition coefficient (P)  drug needs to cross cell membrane  physical measurement with partition between 1-octanol & H2O  P = [drug]oct/[drug]water  low value indicates hydrophilicity  high value indicates hydrophobicity  optimum lipophilicity  when C is concentration of dose  log (1/C) = -k(logP)2 + k’(logP) + k”  lipophilicity contant for substituent (π))  Hansch developed contants for various substituents  π = logPX - logPH  π) > 0, nonpolar substituent  π) < 0, polar substituent o electronic & lipophilicity parameters are additive and constitutive  additive means that they accumulate across the structure  constitutive means they depend on the overall structure o substituent size (sterics)  drug needs to approach target and fit into active or binding site  Verloop parameters calculate size of substituent (STERIMOL)  L = length along bond axis from parent  B1 - B4 = width perpendicular to axis  QSAR equations o Hansch analysis  linear multiple regression analysis  relates biological activity to physicochemical parameters from congeneric series (C=concentration of drug to give specific activity  log 1/C = -a π2 + b π + p + Ces + d o Free-Wilson/Additivity Method  relates biological activity (BA) to effects of substituents (X)  If a substituent is present, X=1; if absent, X=0  a = magnitude of substituent effect,  = activity of parent  BA = ΣaaiXi +  o 3D-QSAR (computer-assisted drug design or CADD)  direct CADD  usually relies on x-ray crystal structure of drug/analog bound in enzyme  co-crystallize drug with target  study specific binding interactions and try to improve  example: HIV protease inhibitor (ritonavir: Abbott) o function of HIV protease: cleaves Phe-Pro bond o x-ray structure is of aspartic protease homodimer with C2 symmetry o design based on C2 symmetry and known aspartic protease inhibitors o first series: symmetrical diamino alcohols  drug fits into flap of drug when bound  initial x-ray shows H-bonds to enzyme  extension of chain allowed for better H-bonding  further changes to improve pharmacokinetics led to ritonavir (1996)  indirect CADD  develop a model of the pharmacophore  need a set of high-affinity ligands  select pharmacophore elements  model to identify low-energy conformers of ligands  superimpose conformers, match elements to give model!  example: D1 agonists o dopamine receptor has D1- and D2-like subtypes o goal was to develop low-energy conformers for D1 subtype o overlap of pharmacophore elements  m- and p-hydroxyls, N, and β-C accessory ring substituent  CoMFA (comparative molecular field analysis)  identify set of compounds with common pharmacophore  generate low-energy conformers  superimpose 3D structures, match elements  establish 3D grid around overlaid structures  calculate steric and electronic fields for each compound in every grid point  generate data table and perform partial least squares o determines minimal set of grid points to explain measured bioactivity  generate 3D structure of steric field  generate 3D structure of electronic field CHAPTER 4: DRUG DEVELOPMENT Pre-Clinical Development-prior to human testing  drug discovery: lead discovery & modification  efficacy  patenting—concurrent with drug discovery o takes 2-5 years, gives exclusive right to sell drug for specified purpose for 20 years o types of patents:  composition of matter: specific compounds  needs to be novel, useful  can file continuation-in-part by adding new compounds to series  process: synthetic procedure  covers method of manufacture  method of use: can be old compounds with new use  example: minoxidil  Rogaine  process development—large-scale synthesis o prepare kilogram quantities o modify original synthesis  efficient (< 10 steps)  cost-effective (reagents, intermediates)  low toxicity of reagents  pilot plant-compatible (avoid chromatography & liquid extraction)  government-regulated  FDA: follow cGMP protocols o regulates sanitation, storage, and testing of intermediates, packaging & labeling o subject to government inspection  toxicology studies o genetic toxicity: check for mutagenicity (ex: Ames test) o acute to chronic in vivo  establish safety and dose levels  acute  single dose: look for signs of toxicity (vomiting, diarrhea, death)  range-finding  2-4 weeks of daily dosing to establish dose levels  sub-chronic o 1-3 months of daily dosing  chronic o 6-12 months of daily dosing long-term dosing (toxicity) o 18-24 months of daily dosing (carcinogenicity)  reproductive toxicity (required after thalidomide)  segment I: fertility, reproductive performance  segment II: teratogenicity, embryo toxicity in early pregnancy  segment III: late pregnancy, delivery, and lactation  pharmacokinetics: ADME studies o parameters:  bioavailability: amount of drug available to act = fraction of drug absorbed intact  distribution: location of drug (blood, tissue)  clearance: ability of body to eliminate drug through metabolism and elimination o ADME studies are done in several animal models  absorption: determines bioavailability, concentration of drug in bloodstream  plot time vs. plasma concentration (calculate AUC)  oral bioavailability = (AUCoral/AUCIV)x100  half-life: time for half of drug to disappear (duration of action)  process of absorption: o stomach (pH = 1-2), approx. 30-60 minutes o small intestine (pH = 5-7), approx. 4-6 hours (most drugs absorbed) o large intestine (pH = 8-8.5) o portal vein  liver (first pass)…most metabolism occurs here o general circulation to target organs  distribution: location of drug  regulated by binding to plasma proteins and transport mechanisms o passive diffusion o active transport o facilitated diffusion  metabolism: chemical changes to drug  reactions carried out by nonspecific enzymes  Phase I: functional group reactions on drug, usually stereospecific o oxidation…cytochrome P-450s o reduction…aldo-keto reductases o hydrolysis of esters & amides…esterases & proteases  Phase II: conjugation to endogenous molecules o enzymes are conjugating enzymes or transferases o glucuronidation  conjugation of glucuronic acid, nucleopphilic attack onto anomeric carbon of UDP-glucuronic acid o glutathione conjugation  nucleophilic endogenous tripeptide o amino acid conjugation  usually glutamate or glycine o N-acetylation o methylation  elimination: how drug is cleared  file IND (investigational new drug) Clinical Development-human testing  Phase I: safety o 20-100 healthy volunteers, usually young males o determine safety and dosing levels, human pharmacokinetics  Phase II: dosing and efficacy o 500 patients o establish dosing and efficacy  double-blind studies (one gets drug, other gets placebo)  Phase III: long-term tolerance, verify efficacy o 1000s of patients o verify efficacy o long-term tolerance o interactions with other medicines o effect in children and the elderly  file NDA (new drug application)  example: development of imatinib (Gleevec) o see powerpoint notes for explanation CHAPTER 5: RECEPTORS receptor = macromolecular complexes that span cell membranes (proteins) exception is for nuclear receptors (intracellular) function: transfer message from outside to inside of cell Receptor Classes:  G Protein-Coupled Receptors (GPCRs)  nuclear receptors  Ligand-Gated Ion Channels (LGICs)  Voltage-Gated Ion Channels (VGICs) Receptor Mechanism:  ligand carrying message binds  causes conformational change in receptor  message is transferred inside cell by effector system  causes change in second messenger  result is activation of enzyme or ion channel to give physiological result Components of Receptor System  ligand: endogenous molecule or drug  receptor: protein complex  effector system: ion channels or G proteins  second messengers: ions (Na+, K+, Cl-), cAMP, DAG, IP3 Ligands: natural or drug  agonist: binds to receptor, causes some defined response  partial agonist: binds to receptor, causes less than full response  inverse agonist: binds to receptor, causes of defined response  antagonist: binds to receptor, causes no response (blocks others from binding) o competitive antagonist: competes with agonist/ligand for binding (same site) o non-competitive antagonist: independent of agonist/ligand concentration (different site)  Two-State Model of Receptor Occupancy o receptor exists in equilibrium between two states: relaxed (ON) and tense (OFF) o agonist binding shifts equilibrium to ON o antagonist binding shifts equilibrium to OFF o partial agonist has partial affinity for both states  Receptor-Ligand terms: o affinity: ability of ligand to bind to receptor, proportional to binding constant o intrinsic activity: proportionality constant of ability of agonist to activate receptor in comparison to standard (defined as having maximum activity) o amino-terminal o DNA-binding (Zn finger, fits into major groove of DNA) o carboxy-terminal  intracellular: upon binding to ligand domain, complex is transported into nucleus  DNA binding results in protein production or suppression  drugs: o agonists:  estradiol o antagonists:  raloxifene…treats breast cancer, osteoporosis  tamoxifen…treats breast cancer  Androgen Receptors o natural ligand: testosterone  5α-dihydrotestosterone o agonist: stanazolol o antagonist: flutamide o non-selective antagonists: cyproterone, spironolactone Hormone Receptors (tyrosine kinase-linked receptors)  3 domains: o extracellular o transmembrane o intracellular  ligand binding causes dimerization and conformational change o intracellular domain autophosphorylates o results in phosphorylation of other proteins  ligands: o insulin o growth factors  protein tyrosine kinase inhibitors o imatinib (Gleevec)…treats CML (chronic myelogenous leukemia)  binds at ATP binding site of bcr-abl kinase  stabilizes active conformer CHAPTER 6: ENZYMES Enzymes  proteins that recognize a substrate and catalyze a chemical reaction  characteristics o substrate specificity (can be broad or specific) o reaction specificity (catalyzes only one type of reaction) o acceleration (rate may be 1010 – 1012 vs. uncatalyzed reaction)  binding interactions: o covalent o noncovalent o stereochemistry  transition state stabilization o enzyme binds the substrate most tightly at the transition state Enzyme Mechanisms  approximation: enzyme is template to bring substrate close to active site  covalent catalysis: nucleophilic amino acid side chain forms bond to substrate o serine (OH) o cysteine (SH) o lysine (NH2)  general acid-base catalysis: proton transfers to increase nucleophilicity of side chain o aspartic acid o glutamic acid o histidine o serine o lysine  electrostatic catalysis/desolvation o desolvation exposes charged groups at active site, stabilize charged transition state  strain/distortion: raises ground state energy to lower the activation energy Reasons for Enzyme Inhibition  diseases arise from excess or deficiency of enzymatic product o vasoconstriction—excess of angiotensin II (inhibit ACE) o Alzheimer’s disease—deficiency of acetylcholine (inhibit acetycholinesterase)  foreign organisms have unique enzymes o HIV virus—HIV protease o bacteria—dehydropteroate synthase (folic acid biosynthesis pathway) Drawbacks to Enzyme Inhibition  inhibiting enzymes needed for metabolic pathways o NSAIDS: inhibit cyclooxygenase—prostaglandin biosynthesis  desired effect: inhibit inflammation caused by prostaglandins  undesired effect: inhibit protection of gastric mucosa by prostaglandins Types of Inhibitors  Reversible o competitive: bind at active site o non-competitive: bind at allosteric site  reduce substrate binding by conformational change to substrate binding site  Irreversible o affinity labeling agents o mechanism-based inactivators (suicide inhibitors)  determine reversible/irreversible based on drug kinetics o competitive: Vmax is eventually reached by increasing substrate concentration o non-competitive: Vmax is never reached by increasing substrate concentration Reversible, Competitive Inhibitors  sulfanilamide antibacterials o discovered in 1935 from azo dyes o lead: prontosil (red dye) o active against Gram-positive bacteria o bacteriostatic o inhibit dihydropteroate synthase (DHP) o drugs:  sulfamethoxazole: inhibit DHP  trimethoprim: inhibits dihyrdofolate reductase  combined with sulfametoxazole (Bactrim)  dapsone: inhibits DHP…treats mycobacteria (M. leprae, M. tuberculosis)  ACE inhibitors o inhibit last step in renin-angiotensin cascade  cleavage of Phe-His bond in angiotensin I (10 AA) to form angiotensin II (8 AA) o angiotensin II causes vasoconstriction, release of aldosterone, degrades bradykinin o discovery  captopril (1981)  enalapril [prodrug converted to enaliprat in vivo] lisinopril o design:  natural product: peptides from snake venom, have C-terminal proline  x-ray was unknown, but it was known to be like carboxypeptidase A  known inhibitor was (R)-2-benzylsuccinic acid  C-terminal proline  Zn binding group (SH or COOH)  hydrophobic pockets (methyl and/pr benzyl) CHAPTER 7: DNA AS A DRUG TARGET DNA Function  replication: copied to form identical daughters  transcription: copied to form RNA (5’ – 3’ direction)  translation: decoded on ribosomes to direct protein biosynthesis DNA Structure  two strands of nucleotide polymers oriented antiparallel in a double helix  A/T (adenine/thymine) form 2 H-bonds  C/G (cytosine/guanine) form 3 H-bonds  aromatic (planar) bases on inside  sugar-phosphate backbone on outside  supercoiling occurs o interconversion mediated by topoisomerase Drug Binding Sites  A/T or C/G pairs in center  sugar-phosphate backbone on outside  major and minor grooves  nucleophilic sites on base pairs o guanine: N7 < O6 o adenine: N1 < N3 o cytosine: N3 Drugs Directly Interacting with DNA  DNA alkylators o nitrogen mustards  derived from sulfur mustards  drugs:  cyclophosphamide o metabolized to form phosphoramide mustard  chlorambucil (Leukaran)…treat Hodgkin’s & Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia  melphalan (Alkeran)…treats multiple myeloma & ovarian cancer o N-nitrosoureas  methylate DNA yields diazonium ion o platins  drugs:  cisplatin  carboplatin  oxaliplatin  DNA intercalators o planar aromatic compounds o bind by π) stacking between base pairs o secondary H-bonding and electrostatic interactions with backbone o unwinds DNA at binding site, interferes with binding of DNA enzymes o important enzymes:  DNA topoisomerase (supercoiling)  Topo II involves cleavage and resealing of strands via cleavable complex  some drugs bind to DNA-Topo II complex  result is lethal double-strand breaks  DNA polymerase (elongation of strand)  intercalation can block progression along DNA strand  some drugs act as antimetabolites and bind to enzyme o drugs: o dactinomycin (actinomycins)  binds DNA at transcription initiation complex  prevents chain elongation by RNA polymerase o daunomycin, adriamycin (anthracyclines)  inhibits topoisomerase o aminophenoxazone (prefers guanines) o cyclic peptides (minor groove), carcinogenic-not widely used o daunorubicin  DNA intercalator/strand breakers o structural features: intercalating region, reactive region o cleave backbone via radical mechanism o drugs:  bleomycin  glycopeptide, couples to copper before being transported into cell  exhanges copper for iron  bisthiazole region intercalates  iron complex binds oxygen, generates radicals at backbone  calicheamycin (enediynes) Drugs Interacting with Enzymes  DNA Processing Enzymes o DNA/RNA polymerase inhibitors  catalyzes formation of phosphodiester bond  nucleoside is phosphorylated by kinases at 5’ position  drug:  Ara-C: mimic nucleoside (arabinose analog of cytidine) o topoisomerase inhibitors  forms transient breaks in DNA strand to allow one strand to pass through another  binds to DNA, forms covalent bond to 3’-phosphate—forms cleavable complex  helix unwinds and 5’ – 3’ bond is re-formed  drugs: o Topo I inhibitors: camptothecins  camptothecin  topotecan  irinotecan o Topo poisons  etoposide analogs—analogs of podophyllotoxin  epimers at 4’ position  stabilize Topo II-DNA complex  glycoside, C & D rings w/DNA; A, B, &, E rings w/enzyme  drugs:  etoposide  teniposide o methyl transferase inhibitors  methylates 5’ position of cytidines (methylation pattern is involved in expression  drug: 5-azacytidines  DNA Synthesis Enzymes o thymidylate synthase inhibitors  converts deoxyuridine to deoxythymidine  Cys146 adds to dump, resulting enolate adds to CH2 of N5-N10- methylenetetrahydrofolate, removal of αH inactivates enzyme  drugs:  5-fluorouracil  prodrugs of 5-fluorouracil: o Tegafur o capecitabine o dihydrofolate reducase inhibitors  drugs:  methotrexate: analog of folic acid, N-methyl analog of aminopterin o inhibits formation of N5-N10-methylenetetrahydrofolate o treats leukemia  raltitrexed (Tomudex)…treats colorectal cancer  premetrexed (Alimta)…treats lung cancer Drugs Affecting Microtubules  microtubules are components of the cytoskeleton o involved in mitosis o polymers of α- and β-tubulin o dynamic instability  assembly and disassembly at ends of microtubules  drugs binding to microtubules affect this polymerization/depolymerization process o binding sites: CHAPTER 8: ANTIVIRALS Drugs Affecting Virus Attachment & Budding  fusion inhibitors o HIV drugs  enfuvirtide (T20)  miraviroc (Selzentry)  neuraminidase inhibitors o influenza drugs  substrate: sialic acid  oseltamivir (Tamiflu): orally administered  zanamivir (Relenza): nasal spray Drugs Affecting Virus Uncoating  disoxaril & analogs o lead: arildone o rimantidine…treats Influenza A o pleconaril…treats enterovirus & rhinovirus o amantidine Drugs Affecting Transcription  nucleosides (traditional): prodrugs phosphorylated by viral or cellular kinases; triphosphate acts as anti-metabolite, then drug is incorporated into DNA/RNA o ribavirin (Virazole)…guanine analog w/modified base…treats RSV o acyclovir (Zovirax)…guanine analog w/acyclic deoxyribose…treats HSV & VSV o gancyclovir (Cytovene)…guanine analog w/ acyclic deoxyribose…treats CMV o entecavir o lobucavir…treats HSV, VZV, CMV, HIV (in humans) o abacavir…treats HIV, active against HIV reverse transcriptase  non-nucleosides (NNRTIs) o nevirapine o efavirenz HIV Therapy  HIV reverse transcriptase inhibitors o nucleosides  azidothymidine (AZT)  dideoxyinosine (ddI)  dideoxycytosine (ddC)  lamivudine (3TC)  abacavir o non-nucleosides (NNRTIs)  nevirapine…originally synthesized as a muscarinic antagonist  efavirenz  etravirine (Tibotec)…active against resistant strains of HIV-1  HIV protease inhibitors…based on C2 symmetry, peptidomimetics…HIV protease is an aspartic protease, so they also screened library for renin inhibitors o amprenavir (Agenerase) o nelfinavir (Viricept) o lopinavir o ritonavir o DuPont-Merck cyclic ureas  HIV integrase inhibitors…cleaves two nucleotides from 3’ end of viral DNA and ligates viral DNA into host chromosomal DNA o raltegravir o elvitegravir o enfurvirtide (mimics as C-terminal segment of gp41 transmembrane segment of glycoprotein)…treats HIV-1 o miraviroc…antagonist for CCR5 CHAPTER 9: CENTRAL NERVOUS SYSTEM DRUGS Drugs for Alzheimer’s Disease (two approaches-cholinergic and amyloid)  cholinergic approach-increase cholinergic function in remaining neurons o donepezil (Aricept)…acetylcholinesterase inhibitor o galantamine (Ramanyl)…acetylcholinesterase inhibitor o rivastigmine (Exelon)…acetylcholinesterase inhibitor o tacrine (Cognex)…acetylcholinesterase inhibitor, N-heptyl amide = Cogmine  amyloid approach-affect plaques of β-amyloid protein o BACE1 inhibitors  CoMentis  Sunesis