Chem4711(SlideSet7)

Chem4711(SlideSet7) - NewDrugDevelopment...

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New Drug Development First, need to choose a disease. Then, need to choose a target. Potentially, could screen for whole cell effects. Better (usually) to choose a specific target. Typically, targets are receptors or enzymes. Need to validate target before attacking it. Does inhibiting target have desired effect in cells/animals?
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Looking for compounds with desired effects. Usually, want to find new small molecules. Exception – growth hormones and regulatory proteins. Need to develop an assay for the target of interest. Should be cheap. Should be amenable to automation. Should be reliable and accurate. Now, ready to screen a large number of compounds Large companies – libraries of >100,000 compounds Can buy libraries of compounds to screen.
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Now, screen compounds. Use your High Throughput Screen (HTS). Identify hits. Verify that they are real. Get potency. Quantitative Structure Activity Relationships For hits, compare structures. See if there are common features. Now, go see your friendly neighborhood medicinal chemist.
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For those compounds that look promising, make analogues. Measure effects on binding/inhibition/activation. Measure effects on whole cells. Some compounds that work on enzymes do not work in whole cells. Some compounds will have severe off target effects. In designing compounds, and thinking about what to test, remembe Lipinski rules History (some functional groups are generally bad actors).
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Lipinski’s rule of 5 Molecular mass should be less than 500 else too big and large to get into cells It should have less than 5 H-bond donors else too polar to pass through membranes It should have less than 10 H-bond acceptors else too polar to pass through membranes It should have a logP of less than 5 else it will not be soluble in water
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This was the easy part! Generally, will end up with a number of interesting compounds. Need to guess who will do best when you push forward. Use history as your guide. Consider synthetic problems (g synthesis vs. 100 kg synthes Consider metabolism. Once you have made you choice, open up the checkbook.
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Begin animal screening. Start small, work your way up (small = cheap).
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This note was uploaded on 02/23/2011 for the course CHEM 4711 at Colorado.

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Chem4711(SlideSet7) - NewDrugDevelopment...

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