Med Chem Final Review PDF

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Important concepts to remember for Finals and PCOA...

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Dr Hulme email - The following is guidance for the final: ● 61 questions total. There will be two questions/lecture (i.e. 50 questions). ○ It is prudent to prioritize key take home points of each lecture in your learning. ○ Occasionally you will find some questions that are similar to questions previously asked, yet they will be constructed from a slightly different viewpoint. ● The remaining 11 questions will be from me. As such split between basic principles and PCOA style structural recognition questions. ● Basic principles ○ These will be take home messages that have been mentioned multiple times. ○ Reviewing previous quizzes from 837A and 837B will be an initial good starting point in your studies, followed by a high level review of the first 5 lectures. ● Structural recognition ○ I have certain favorites I believe are classics in recognition and I hope PCOA would think the same. As such, I recommend the following drugs/classes for study/recognition and hopefully long-term memory retention. ■ a) A statin ■ b) Aspirin ■ c) Ibuprofen ■ d) Celebrex ■ e) Haloperidol and associated metabolism ■ f) Tylenol and associated metabolism ■ g) Fluoxetine ■ h) Methamphetamine ■ i) Local anesthetics in general (i.e. lidocaine). ■ j) ARBS (i.e. Losartan) ■ k) Plavix ■ l) Cocaine ■ m) Abilify ■ n) Warfarin

One of the ED questions will focus solely on Sildenafil SAR. Understanding its binding mode and being able to rank order molecules for affinity is essential.

Drug

Structure

Sildenafil

SAR

Binding Mode

Rank order for affinity

Contains 4 regions: - hydrophobic pocket - lid: piperazine - interacts with surrounding hydrophobic residues - core - metal binding site

Engages Zn and Mg through a water network

Levitra - med T1/2

Engages invariant glutamine via donor and acceptor

Viagra - med T1/2, also inhibits PDE6 (vision blue-green shift)

Cialis - longer T1/2, improved selectivity for PDE5s

4/30/19 lecture: questions/concepts on final

Q) What cancer drug would you add to reverse process of protein degradation? A) A proteasome inhibitor, Bortezomib (Velcade).

Hulme said there will be 2 questions on final about kinase inhibitors

*Hulme said during class 2 questions on final about kinase inhibitors*

Type 1 (DFG-in) ● BCR-Abl inhibitors - Chronic Myeloid Leukemia ○ Dasatinib ○ Bosutinib ● Tyrosine Kinase inhibitors - Non-small cell lung cancer ○ Tarceva (Erlotinib) ○ Iressa (Gefitinib) Type 2 (DFG-out) ● BCR-Abl inhibitors - Chronic Myeloid Leukemia ○ Gleevec (Imatinib) ○ Tasigna (Nilotinib) ○ Iclusig (Ponatinib) ● BRAF inhibitor - renal cell carcinoma ○ Nexavar (Sorafenib) ● Lipid Kinase inhibitor ○ Idelalisib (only LKI) Type 3 - metastatic melanoma ● Trametinib (only type 3 inhibitor)

Type 1 inhibitors better able to cross BBB (can use for brain disorders) - lower MW, fewer NH groups, better logP, PSA closer to 70A2 Type 1: no pharmacophore, uses Traxler Binding Model Type 2: “mother of all pharmacophores”

Lecture Review (2 questions per lecture - 50 questions)

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Topic

Key points

1

Anti-cancer (Hulme)

Every kinase has an active form (phosphorylated) and 2 inactive forms (DFG-in and DFG-out, both are not phosphorylated). Most drugs inhibit the active form or inactive (DFG-out) form of a kinase (types 1 and 2 respectively) 2. Type 1 - ATP competitive (orthosteric), inhibit active form (DFG-in) - bind to ATP site directly 3. Type 2 - Allosteric “that disrupt ATP binding” (DFG-out, inhibit inactive form - indirectly competing w/ ATP a. Type II inhibitors DFG out= inactive form of kinase 4. Essential interaction for Type 1 kinase inhibitor= interaction w hinge region (via 1-3 H bonds) a. Phosphate binding region interacts with conserved lysine b. Type 1 inhibitors target the ATP site in its active conformation with the activation loop phosphorylated 5. The gatekeeper residue (threonine) is the easiest to be mutated (to isoleucine [about a methyl group longer]) -> poor fit and loss in activity 6. Type 2 has 6 or 7 pharmacophore figures (containing Hinge RB, Linker, and hydrophobic motif) 7. Trametinib= only type 3 inhibitor, does not bind to the hinge 8. BCR-Abl inhibitor a. Imatinib= type 2 inhibitor meaning DFG-out, inactive form of BCR-Abl (flag methyl essential for selectivity) i. Interacts with conserved lysine through water network ii. Nilotinib and Ponatinib type 2 inhibitors designed from imatinib to address emerging resistance to T315I b. Dasatinib and Bosutinib = type 1 inhibitor 9. Tyrosine kinase inhibitors (EGFr) a. Gefitinib and erlotinib= type 1 inhibitor (quinazoline scaffold) 10. BRAF inhibitor a. Sorafenib = type 2 inhibitor 11. Irreversible inhibitors= alpha beta unsaturated bond = afatinib, imbrutinib a. Has michael acceptor 12. Type 1 is good for targeting glioblastoma or neurodegenerative diseases because lower molecular weight and only 1 H donor.

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Anticancer (Sun)

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3

Anticancer(Sun)

1.

2 types of cancer treatment a. Cytotoxic agent (target cell division/DNA) i. DNA alkylating agents, antimetabolites, natural products, topoisomerase inhibitors b. Molecular-targeted agents (target molecular abnormality) - higher therapeutic index (safer) i. Monoclonal antibodies [ Herceptin, Avastin ] ii. Tyrosine kinase inhibitor [ Gleevec ]

Interaction of nitrogen mustard with DNA a. Aziridinium ions are the alkylating species from chlorambucil, mustine (chlormethine), and cyclophosphamide b. Methyldiazonium ions are the alkylating species for carmustine, lomustine, and ethylnitrosourea (N-alkyl-NNitrosourea compounds) as well as temozolomide and dacarbazine (diazo/triazo compounds) Platinum compounds (cisplatin, carboplatin, oxaliplatin)

a. metal coordinate complexes that cause monoalkylation or crosslinking of DNA Antimetabolites (8-azaguanine, 6-mercaptopurine, azathioprine) a. Resemble purines and compete for biosynthesis or utilization of purine metabolites b. Triphosphate forms can be incorporated into growing RNA/DNA 5-fluorouracil is an antimetabolite of uracil a. Activated by anabolism to FdUMP which is a thymidylate synthase inhibitor (suicide inactivation) b. Capecitabine is prodrug of 5-FU Gemcitabine a. Diphosphate form is strong inhibitor of ribonucleotide reductase b. Triphosphate form replaces dCTP during DNA replication → DNA synthesis stops → tumor growth stops → apoptosis c. Pancreatic cancer Methotrexate is a DHFR inhibitor (pseudo-irreversible), inhibiting DNA synthesis in the S phase 4

Anticancer 3

Natural products DNA-interactive drugs (actinomycin, bleomycin) a. Has 3 main domains: metal binding domain, carbohydrate domain, DNA binding domain b. Bleomycin chelated with iron binds to DNA and may create free radicals, causing cleavage of phosphodiester bonds DNA-topoisomerase poisons (anthracyclines - doxorubicin & epirubicin, etoposide camptothecin, topotecan, irinotecan) a. Topo II poisons intercalate into DNA and prevent replication b. Cardiotoxicity from doxorubicin occurs through ROS production and possibly cellular iron accumulation c. Etoposide stabilizes DNA-topo II complex d. SAR Topo I inhibitors (camptothecin, topotecan, irinotecan) i. Planar pentacyclic ring with lactone in ring E is essential for activity e. Irinotecan = prodrug Tubulin-interactive compounds (vinca alkaloids - vincristine & vinblastine, taxol) a. Vinca alkaloids block polymerization of tubulin to microtubules i. They’re complex structures: indole-containing moiety, catharanthine b. Paclitaxel blocks depolymerization of microtubules into tubulins i. A tetracyclic 17-carbon (heptadecane) structure

5

Anticancer 4

Antibodies Herceptin (trastuzumab) and Perjeta (pertuzumab): humanized anti-HER2 mab a. Both induce antibody dependent cellular cytotoxicity Epidermal growth factor receptor targeted therapy a. Cetuximab & panitumumab inhibit EGFR-mediated intracellular signaling by binding to EGFR and dimerizing Tumor angiogenesis inhibitor a. Avastin (bevacizumab) targets VEGF (angiogenic factor) which decreases blood supply to the tumor B cell targeting Mabs a. Rituximab & ofatumumab b. Both are antibodies against protein CD20 found on surface of immune B cells (treat cancers with excessive numbers of B cells such as leukemias or lymphomas) Immune modulating agent a. Ipilimumab augments T cell activation and proliferation by binding CTLA-4 and preventing interaction with ligands (CD80 and CD86) Programmed death receptor (PD-1) inhibitors

a.

Nivolumab and pembrolizumab block PD-L1 from binding to PD-1, resulting in reactivation of T cell mediated tumor cell killing Proteasome inhibitor a. Bortezomib is a peptidomimetic with a boronic acid “warhead” which interacts with the proteasome very tightly 6

Anticancer 5

7 8

Intro to CNS

a. b. c. d. e. f.

9

Anti-Psych

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BBB penetration: logP 2-4, PSA PSA>>clogP B/P=Brain plasma ratio of drug Do not count buried hydrogen bond- not on surface of molecule CNS MPO>=4 P-glycoprotein efflux related to residency time in the lipid bilayer

ABA pharmacophore (aromatic-base-aromatic) Ki D2/ KI 5HT2A >>1 for atypicals (moderate D2 blockade with potent 5-HT2A blockade minimizes EPS) ○ Benzazepines - clozapine, olanzapine, quetiapine ■ Clozapine causes agranulocytosis, significant weight gain (due to 5-HT2C antagonism) ■ Quetiapine has tail that enhances solubility, causes lower weight gain, less tendency to cause seizures ○ Benzisoxazoles/benzthiazoles - risperidone/ziprasidone ■ Ziprasidone prolongs QT interval and possible onset of ventricular arrhythmia ■ Risperidone causes loss of libido ○ Arylpiperazines - aripiprazole ■ Superior side effect profile ■ Extra action through partial agonism of D2 autoreceptors KiD2/Ki5HT2A N-demethylation - Maprotiline is technically a tetracyclic compound with a 2-carbon bridge and secondary amine TCA properties SSRI- fluoxetine, citalopram, etc SAR: 4-substituted aromatic ring convers 5-HT reuptake inhibition, 2-substituted aromatic ring confers NE reuptake inhibition. Four atoms between base and aromatic group is critical. SARI - trazodone Has SSRI-like activity and antagonism of 5-HT2A Major metabolite via oxidative deamination is MPP (active, 5-HT2C agonist) Can cause idiosyncratic hepatotoxicity and priapism in men Norepi & Dopamine Reuptake Inhibitor - bupropion The tert-butyl is not easily removed (little central stimulant activity, no pressor activity) No weight gain, no sexual dysfunction Serotonin Receptor Modulators - nefazodone, mirtazapine, venlafaxine Nefazodone developed from trazodone but is less sedating and no priapism issues. Potent inhibitor of CYP3A4. Acts as SSRI and antagonist of 5-HT receptors. Metabolism via oxidative deamination. Low dose venlafaxine acts as SSRI and high dose acts as Norepinephrine reuptake inhibitor norepinephrine/serotonin reuptake inhibitors - duloxetine Optimization of SSRI pharmacophore with bioisosteres (introduction of naphthalene & thiophene) 11

Antidepressants 2

12

Anti-Parkinson

Cell death in nigrostriatal pathway leads to breakdown of signaling pathway and TRAP movement disorders In the periphery, COMT breaks down levodopa and DDC activates levodopa to dopamine In the CNS, COMT and MAOB help break down levodopa and DDC helps to activate it to dopamine Goal is to keep dopamine around longer, mimic it, block dopamine degradation, use anticholinergics to balance levels of Ach and dopamine Carbidopa - does not cross the BBB and irreversibly inactivates DDC in the periphery. This is good because we don’t want dopamine to be formed in the periphery. Use levodopa as well to help promote more conversion into dopamine S enantiomer is active, is a hydrazine based DDC inhibitor Selegiline and Rasagiline - MAOB suicide inhibitors Covalent adduction to MAOB (has a Michael acceptor) Tolcapone and Entacapone - COMT reversible inhibitors (nitro-catechol critical for affinity) Tolcapone - blocks both peripheral and CNS COMT Entacapone - inhibition of peripheral COMT only

Can use anti-muscarinics - atropine or benztropine Apomorphine is a conformationally constrained analog of DA (trans), a potent agonist (lipophilic enough to pass BBB) but undergoes significant first pass metabolism and severe side effects

Remember: aromatic-base-aromatic 13

Hallucinogens/drugs of abuse

Cannabinoids MOA is CB1 agonism THC is active ingredient Aromatic-hydrophobic-hydrophobic pharmacophore The phenolic OH group acts as acceptor if CB2 selective, acts as donor if CB1/CB2 dual agonism Major metabolic soft spot is the methyl on the A ring B ring can be opened and retain THC-like activity Rimonabant is selective CB1 antagonist for overweight/obesity to stop hunger PCP (phencyclidine) and related agents Aromatic-base-hydrophobic pharmacophore PCP is an NMDA antagonist Ketamine is also an NMDA antagonist for instant alleviation of suicidal thoughts Hallucinogens LSD is an indolealkylamine, 5-HT2A agonist (embedded serotonin in structure) Amphetamine and methamphetamine are phenylalkylamine hallucinogens and are 5-HT2A agonists

Central stimulants Phenylisopropylamines are central stimulants, promoting the release of dopamine through inhibition of VAT (SAR below) Cocaine is a central stimulant - a tropane. MOA: blocks NET & DAT. Cocaine pharmacophore: base-accepter-hydrophobic. Designer drugs MDMA (ecstasy) is also a phenisopropylamine but is a triple reuptake inhibitor

14

PDE Drugs

PDE4 inhibitors (cilomilast, piclamilast) 4 point pharmacophore: hydrophobic-acceptor-acceptor-acid Acid or pyridine N = metal binding region, hydrophobic group sits in hydrophobic pocket, 2 acceptors interact with the invariant Gln PDE5 inhibitors (sildenafil = Viagra, tadalafil = Cialis) Sildenafil ADE is the blue → green color shift due to inhibition of PDE6 in the eye Sildenafil engages invariant glutamine with bidentate interaction Tadalafil engages invariant glutamine with monodentate interaction and does not utilize the lid or metal binding region Tadalafil: the diketopiperazine (DKP) moiety can be completely removed or replaced with other heterocycles Metabolism via 3A4 (COMT O-dealkylation then glucuronidation). Cialis has longer T1/2. DDIs with 3A4 inhibitors, organic nitrates (contraindicated), grapefruit juice, entacapone (COMT inhibitor)

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15

Anti-emetic

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16

Sedatives

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5HT3 antagonists (Granisetron) were developed from cocaine All have common 3 pt pharmacophore: aromatic, acceptor, base (do not confuse with ABA in CNS drugs) 5HT3 antagonists structurally fall into two classes: tropane like and imidazole like ○ Tropane-like: granisetron, dolasetron, palonosetron ○ Imidazole containing: ondansetron, alosetron Additional SAR of phenothiazine D2 receptor antagonist = compatibility of N-methyl-piperazine that encompasses the tertiary amine (before, the tertiary amine alone was critical) ○ Butyrophenone class of D2 antagonists (droperidol and haloperidol) for PONV Metoclopramide is a D2 antagonist that at higher doses also antagonizes 5-HT3 and retains the 5-HT3 pharmacophore Key pharmacophore and privileged motif embedded in anti-histamines? Aromatic-base-aromatic and the diphenylmethane motif

SAR Barbs ○ Alkyl or aryl at C5 are required (aromatic=more hypnotic) ○ Short chain resists oxidation (longer half life), long chains are readily oxidized (shorter half life) ○ Multiple bonds in alkyl substituents are more readily oxidized, shorter duration ○ Polar groups (OH, NH2, COOH) to the 5 alkyl or aryl substituent decreases lipid solubility and potency ○ Aromatic substituted analogs are more hypnotic than aliphatic substituents but only one substituent should be a closed chain for good hypnotic activity ○ Alkylation at N1 or N3 increases lipid solubility - greater hypnotic potency and shorter onset/duration ○ Replacing oxygen with sulfur at C2 increases lipid solubility, greater hypnotic potency, shorter onset/duration but more sulfur at C4 or C6 decreases activity Thiopental ○ CYP3A4, general anesthesia, short DOA→ rapid redistribution away from central circulation towards muscle and fat tissue Thiamylal ○ Surgical anesthesia, Short acting Ramelteon ○ Constrained analogue of melatonin, effective in initiating sleep (but not maintaining), does not depress cognitive function, memory, or ability to concentrate Suvorexant: Blocks Orexin A and orexin B Benzos ○ Clonazepam: anticonvulsant, panic disorder ○ Alprazolam: anti anxiety, panic disorder ○ Diazepam: anticonvulsant, muscle relaxant, anti-anxiety, alcohol withdrawal SAR Benzos ○ No subs @6,8,9 is required ○ EW group (halogen or nitro) @7 is required ○ Oxygen, sulfur, or nitrogen @2 may interact w HBD groups at receptors ○ Alkyl subs @3 decreases activity ○ If 4.5 double bond is saturated or shifted to 3,4 decreases activity

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17

Hypnotics

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Insulin

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Flurazepam ○ Partial agonist, CYP3A4, long t ½ Quazepam ○ Selectively targets a1 of GABAa Benzo triazole t ½ ○ Estazolam>Alprazolam>Estazolam Zolpidem ○ Type 1 GABAa a1 Eszopiclone ○ Not as specific for a1 GABAA, long t ½

Protamine: low molecular cationic protein that prolongs insulin’s effect by decreased absorption (NPH insulin); Zinc added in insulin prolongs duration of action.

Nonhexameric insulins: developed to block formation of insulin dimers and hexamers w/o altering receptor binding ● Insulin Lispro (Humalog)- reversing penultimate Lysine and Proline residues on C-terminal of end B chain ● Insulin Aspart (Novolog)- replacing Proline at B28 with Aspartic acid residue ● Insulin Glulisine (Apidra)- replacing Lysine at B29 with Glutamic acid and Asparagine at B3 with Lysine

Long acting insulins: a shifted isoelectric point Insulin glargine (Lantus) and acylated insulins (Determir and Degludec) ● Arginine amino acids shifts IP from pH 5.4 to 6.7 ● Designed to bind to albumin, binding protracts absorption of insulin from subcutaneous depot 19

Oral Hypoglycemics

20

Intro to Steroids

Endogenous: ● Hydrocortisone [cortisol] ● 17�-estradiol (� = substituent oriented towards the top surface) ● Testosterone Synthetic: ● Dexamethasone ○ OH @ position 11 - Essential for receptor binding ● 17� -ethinylestradiol (� = substituent oriented towards the bottom surface) ○ Metabolic shield in structure to block metabolic inactivation of hormone (extends duration of action) ● 17� -methyltestosterone ○ Metabolic shield in structure to block metabolic inactivation of hormone (extends duration of action) Cyclopentanoperhydrophenanthrene -- parent compound of steroids Testosterone -- aromatase ---> estradiol (Aromatase is a drug target) Estrogen Receptor: Ligand-activated transcription factor

21

Estrogens

Endogenous Estrogens: ● Estradiol (E2) -- low bioavailability due to rapid hepatic metabolism into E1 & E3 ● Estrone (E1) ● Estriol (E3) ● Potency: E2 > E1 > E3 SAR: Estrogens ● Aromatic A ring; C3 OH group ● 17� - OH group ● Distance between C3 & C17: 10.3 to 12.1 ● Planar hydrophobic scaffolding (no bends) ● Unsaturation in B ring enhances estrogenic potency ● 17� -ethinyl & 17� -vinyl substituent: oral availability through inhibition of D-ring directed metabolic inactivation.

Estradiol ester prodrugs: for IM administration; duration of action 14-28d 17� -ethinylestradiol [EE]: metabolically stable, oral estradiol ● 17� -ethinyl substituent: ○ Ethinyl group does no...