Routes to discovery. For each of the following drugs, indicate whether the physiological effects of the drug were known before or after the target was identified.

Lipinski’s rules. Which of the following compounds satisfy all of Lipinski’s rules? [Log(P) values are given in parentheses.]

Calculating log tables. Considerable effort has been expended to develop computer programs that can estimate log(P) values entirely on the basis of chemical structure. Why would such programs be useful?

An ounce of prevention. Legislation has been proposed that would require that N-acetylcysteine be added to acetaminophen tablets. Speculate about the role of this additive.

Clinical-trial design. Distinguish between Phase I and Phase II clinical trials in regard to number of persons enrolled, the state of health of the subjects, and the goals of the study.

Drug interactions. As noted in this chapter, coumadin can be a very dangerous drug because too much can cause uncontrolled bleeding. Persons taking coumadin must be careful about taking other drugs, particularly those that bind to albumin. Propose a mechanism for this drug–drug interaction.

A bad combination. Explain why drugs that inhibit P450 enzymes may be particularly dangerous when used in combination with other medications.

Mechanistically speaking. Name one advantage of a noncompetitive inhibitor as a potential drug compared with a competitive inhibitor.

A helping hand. You have developed a drug that is capable of inhibiting the ABC transporter MDR. Suggest a possible application for this drug in cancer chemotherapy.

Find the target. Trypanosomes are unicellular parasites that cause sleeping sickness. During one stage of their life cycle, these organisms live in the bloodstream and derive all of their energy from glycolysis, which takes place in a specialized organelle called a glycosome inside the parasite. Propose potential targets for treating sleeping sickness. What are some potential difficulties with your approach?

Knowledge is power. How might genomic information be helpful for the effective use of imatinib mesylate (Gleevec) in cancer chemotherapy?

Multiple targets, same goal. Sildenafil induces its physiological effects by increasing the intracellular concentrations of cGMP, leading to muscle relaxation. On the basis of the scheme shown in Figure 36.17, identify another approach for increasing cGMP levels with a small molecule.

Variations on a theme. The metabolism of amphetamine by cytochrome P450 enzymes results in the conversion shown here. Propose a mechanism and indicate any additional products.

HIV protease inhibitor design. Compound A is one of a series that were designed to be potent inhibitors of HIV protease.

Compound A was tested by using two assays: (1) direct inhibition of HIV protease in vitro and (2) inhibition of viral RNA production in HIV-infected cells, a measure of viral replication. The results of these assays are shown below. The HIV protease activity is measured with a substrate peptide present at a concentration equal to its K_M value.

Estimate the values for the K_I of compound A in the protease-activity assay and for its IC₅₀ in the viral-RNA-production assay.

Treating rats with the relatively high oral dose of 20 mg kg⁻¹ results in a maximum concentration of compound A of 0.4 µM. On the basis of this value, do you expect compound A to be effective in preventing HIV replication when taken orally?