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Skip to 0 minutes and 10 seconds DAVID MANALLACK: So far, we’ve seen an evolution take place in this story of drug discovery. The next part of this presentation will take you through the molecular changes that have been made. The importance of this work has been to provide safe and clinically effective medicines. If side effects are apparent, well where there’s too much variation in the effect of a drug from one person to another, then improvements must be made. The story of the sulfonamides, evolving to the sulfonylurea compounds, is a classic process of continual improvement. And all of this is oriented to providing better medicines for better health outcomes.

Skip to 0 minutes and 53 seconds From sulfanilamide, the next development was to change the right hand side to produce IPTD. From there, we developed the first sulfonylurea with a short carbon chain attached to the right hand side. Tolbutamide was next, and it gave us reduced toxicity and was much more specific for treating diabetes.

Skip to 1 minute and 21 seconds The chlorine atom in chlorpropamide reduced the metabolism of the drug, giving it a long half life. The next generation of compounds includes glibenclamide, with its significantly modified left hand side. Glipizide shares a similar left hand side, and the identical hydrophobic right hand side for the molecule. Finally, we arrive at gliclazide, with a return to a methyl group on the left hand side, which we first saw in tolbutamide back in the 1950s. So to some extent, we’ve come full circle while the right hand side retains the need for a hydrophobic group.

Skip to 2 minutes and 11 seconds Unfortunately, we don’t have structural information on the protein target of gliclazide. The structure of gliclazide is shown here in this animation, illustrating the overall shape of this molecule. And we see it here rotating around, demonstrating its overall structure.

Skip to 2 minutes and 34 seconds So let’s review what we’ve covered in this chemistry module. A drug’s side effect is what led to the development of the sulfonylurea antidiuretic drugs. Indeed, drug side effects have often been exploited to develop new medicines. And the most famous case is that of Viagra. We looked at the molecular features needed for biological activity as well as those that could be modified to improve drug safety for the sulfonylurea drugs. And indeed, both the left and the right hand sides of these molecules were modified to create clinically useful compounds.

Diabetes chemistry: part 2

Watch David explain the process of optimising the chemical structures of the anti-diabetic sulfonylureas for safety and efficacy.

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