203f99_e3key

203f99_e3key - Chemistry 203 Lg (Fall 99) Quiz #3 November...

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Unformatted text preview: Chemistry 203 Lg (Fall 99) Quiz #3 November 16, 1999; 11:00-11:50 am. Professor Charles E. McKenna IN IAL OF AST NAME Please do not open this exam until you are told to do so. Write legibly to avoid confusion. GOOD LUCK ! ! Maximum Question # ’ . Score Grader Pomts 21-25 Stude t Signature Circle the most nearly correct answer for each question. (4 Pts.) 1. Which is not true? A “lead compound” for drug development: —- shows a desired, useful biological activity — contains the element Pb (plumbium, “lead”) — may be found in a natural herbal remedy — may be a novel synthetic compound 2. Development of a new drug based on a natural source includes the following steps: 1. Design/synthesis of improved novel drug structures 2. Make structural analogs and determine structure-activity relationships 3. Isolation of active compound from most active natural source 4. Screen natural sources for biological activity The logical order would be: — l, 2, 3, 4 Q 4,3,2,1 — 3,4,l,2 — 2,1,3,4 3. Consider the possible drug — receptor interactions ABCD shown below. The real drug (free = OH group), binds tightly to its receptor (highly active). When converted by metabolic enzymes to its O—Me form, retains its full activity. These observations taken together are consistent with: /; 4. Changes in a drug structure that might tend to increase binding efficiency of a pharmacophore (active region of drug structure) O to m \ / \ __ / = t /C R ° 4?. E.“ CI-I(CH3)2 to CH3 All of the above Given that a drug has essential structural parts that confer biological activity, we could simplify the structure, conserving the key parts, to reduce the cost of manufacture. The likely trade-off in this approach: less selectivity and fewer side effects less selectivity and more side effects more selectivity and more side effects more selectivity and fewer side effects A drug taken orally, to be effective when taken in a single daily dose, must: react with stomach acid resist absorption by the gastrointestinal tract be easily broken down in the liver none of the above are true In general, a drug: should be as lipophilic as possible needs a - (negative) charge to cross hydrophobic membranes may be inactivated by body enzymes that oxidize drug R—CH3 groups to R-CHZOH should be highly toxic to human cells .luwwwrufim'awmwymfiw‘WW ‘ ffiW‘flv‘l/N:wém:mull» _ A it“, came.» watts“, «n- w. 8. To be most effective, drugs should have: '— a very short half-life in the bloodstream — a very long half-life in the bloodstream -— a very high solubility in water @ a moderate half-life in the bloodstream and a balance of water— and fat-solubility 9. According to the diagram, "B": RECEPTOR l RECEPTOR 2 G Selectively binds to receptor 1 —— Selectively binds to receptor 2 - Binds to both receptors —- Binds to neither receptor 10. QSAR means — Qualitative Structure - Activity Relationships —- Quantum Stereochemical Activity Relationships - Quantum Structural Activity and Reactions — \ Quantitative Structure — Activity Relationships 11. A series of drug analogs A, B, C showed partition coefficient (P) values of A, 1; B, 10; C, 100. The effective concentrations (C) for activity were: A, .0001; B, .01; C, 1. Our results m that, in this series: 69 a more hydrophilic analog has more activity a more hydrophobic analog has more activity — a plot of log (l/C) vs. log P will have a positive slope — hydrophobicity of the drugs does not affect their activity. 12. In a typical QSAR graph, P refers to a drug’s: Q solubility in octanol / solubility in H20 - solubility in H20 / solubility in octanol — solubility in H20 — solubility in octanol 13. A Daily Trojan reporter studied records on illegal use of handicapped parking in the Westwood Village area. She found that the mean frequency leapita for UCLA football players was three standards deviations higher than that for a control group:) — these results establish a causal relationship between the two sets of data — the difference is not highly significant because the number of standard 14. caused no toxicity in an animal model (10 animals 0 15. deviations is too small these results indicate a highly significant difference between the two sets of data A sample of 100 AIDS patients in Phase trials were given an experimental drug which We can prudently conclude that: the drug is safe and will be non-toxic the AIDS patient study will never see toxicity in a Phase II trial the drug has the same toxicity for humans vs. animals Although the drug appears safe, we cannot rule out side effects until the s end of the Phase II study As suggested in the diagram: the drug L—Dopa crosses the blood Blood Brain Cells brain barrier thanks to its low Suppy polarity the prodrug L-Dopa crosses the blood brain barrier using an amino acid transport system, then is H,~ coon activated by an enzyme to release the drug Dopamine in the brain “3°93 the prodrug Dopamine crosses the blood supply barrier using an amino acid transport system, then is activated by an enzyme to release the drug L—Dopa in the blood supply The drug L-Dopa gets a “piggyback ride” through the blood brain barrier because it is attached to an amino acid 16. A drug company gets an NDA approved for its hot new drug by the FDA. It is now: - ready to start toxicology studies in an animal model — ready to start Phase I clinical trials — ready to start Phase III clinical trials @ ready to sell the drug on the market /’ A! 17. A problem in shortening the time devoted to the Phase II — Phase II clinical trials of an AIDS drug is: /‘ — may not get any results on efficacy 9 long-term side effects may be missed — drug resistance may appear more rapidly — precludes double—blind study 18. In a small clinical trial, only six (6) patients are enrolled in the group receiving a test drug. At the end of the trial, they show a mean decrease in viral load of 30% relative to the control group, with statistic “t” = 2.01. The probability that the difference was observed solely by chance is ' a 5% — . 0.5% -— 95% — 99.5% (HINT: see table on following page.) 19. Effective drug dose levels depend on: — gender — ethnicity — age / a all of the above Area t Area to the right Degrees of ' 1 6.314 12.706 31.821 63.667 2 2.920 4.303 6.965 9.925 3 2.353 3.182 4.541 5.841 4 2.132 2.776 3.747 4.604 5 2.015 2.571 3.365 4.032 6 1.943 2.447 3.143 3.707 7 1 .895 2.365 2.998 3.499 .-. 8 1.860 2.306 2.896 3.355 9 1 .833 2.262 2.821 3.250 10 1.812 2.228 2.764 3.169 11 1.796 2.201 2.718 3.106 12 1.782 2.179 2.681 3.055 13 1.771 2.160 2.650 3.012 14 1.761 2.145 2.624 2.977 15 1.753 2.131 2.602 2.947 16 1.746 2.120 2.583 2.921 17 1.740 2.110 2.567 2.898 18 1.734 2.101 2.552 2.878 19 1.729 2.093 2.539 2.861 20 1 .725 2.086 1 .528 2.845 21 1.721 2.080 2.518 . 2.831 22 1.717 2.074 2.508. 2.819 23 1.714 2.069 2.500 2.807 24 1.711 2.064 2.492 2.797 25 1.708 2.060 2.485 2.787 26 1.706 2.056 2.479 2.779 27 1 .703 2.052 2.473 2.771 28 - 1.701 2.048 2.467 2.763 . 29 1.699 2.045 2.462 2.756 30 1.697 2.042 2.457 . 2.750 40 1.684 2.021 2.423 2.704 60 1.671 2.000 2.390 2.660 76 20. Before entering a clinical trial, we need to have the following information about a new drug, except: — chemical composition and source — animal acute toxicity data a preliminary efficacy data for patients — names and credentials of physicians who will be in charge 21. “Placebo effect” refers to — patients showing a negative result despite a positive drug control (older effective drug) — patients showing a positive result from a positive drug control (older effective drug) — physicians diddling their clinical trial results to please a sponsoring drug company 0 patients showing a positive result from a negative (non-effective) drug control like starch tablets 22. A newspaper report says that a new drug is “100% more effective” than a competing d . To evaluate this claim, we would also need to know: 4 ‘ the confidence level for a difference of 100% — the toxicity of one of the two drugs — the degrees of freedom for the statistic — the z value for at least one subject 23. Referring to the diagram showing two pH—dependent forms (A, B) of a drug, it is more likely that: O A crosses membranes, B binds to the receptor site — B crosses membranes, A binds to the receptor site — A and B cross membranes, only A binds to the receptor site -— Only B crosses membranes and binds to the receptor site 24. When we increase the number of patients in a clinical trial, we want to: 9 Increase the number of degrees of freedom — Increase the statistic t I — Increase the sample standard deviation 3 — Change the population mean, u, 25. Examples of drug metabolic reactions include: — Hydrolysis of esters and amides — Oxidations of exposed methyl groups to CHZOH — Activation of the anticancer drug cyclophosphamide All of the above BONUS QUESTION! (plus 4 points) Explain briefly (one sentence) why so few AIDS (or any other) drugs (“<1/5000”) that appear promising in lab tests at the enzyme level fail to reach the clinic for prescription to patients. 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203f99_e3key - Chemistry 203 Lg (Fall 99) Quiz #3 November...

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