Raltalgvir LO

HIV-Integrase was also discovered as another method of disrupting viral replication in host cells. Merck were working on multiple viral targets and had quality lead compounds, including inhibitors for Hepatitus-C. Combining leads into one series initial appeared unfruitful and the reason for doing this appears unclear. It is usual in anti-infective programs to measure IC95 inhibition, and also at assays containing blood serum, which can suppress the activity as free concentration of active compound is reduced. Without high virus suppression replication continues and the drug has next to no effect. This program is an illustration of a chemical series that was highly bound to blood proteins: an acidic core scaffold and a lipophilic aryl group, being the driver for this. The authors took the approach of looking at another part of the molecule, where polar groups can be added to modulate the blood protein binding. SAR exploration yielded two groups that resulted in candidate drugs.

Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection.

J. Med. Chem. 2008, 51, 18, 5843–5855

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